3,6-Bridged 9,12-oxolides

ABSTRACT

The present invention discloses compounds of formula (I) or pharmaceutically acceptable salts, esters, or prodrugs thereof:  
                 
which exhibit antibacterial properties. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject in need of antibiotic treatment. The invention also relates to methods of treating a bacterial infection in a subject by administering a pharmaceutical composition comprising the compounds of the present invention. The invention further includes process by which to make the compounds of the present invention.

RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No.60/786,867, filed on Mar. 29, 2006. The entire teachings of the aboveapplication are incorporated herein by reference.

TECHNICAL FIELD

The present invention relates to novel semisynthetic macrolides havingantibacterial activity that are useful in the treatment and preventionof bacterial infections. More particularly, the invention relates3,6-bridged 9,12-oxolide compounds, compositions containing suchcompounds and methods for using the same, as well as processes formaking such compounds.

BACKGROUND OF THE INVENTION

The spectrum of activity of macrolides, including erythromycin, coversmost relevant bacterial species responsible for upper and lowerrespiratory tract infections. 14-membered ring macrolides are well knownfor their overall efficacy, safety and lack of serious side effects.Erythromycin however is quickly degraded into inactive products in theacidic medium of the stomach resulting in low bioavailability andgastrointestinal side effects. Improvement of erythromycinpharmacokinetics has been achieved through the synthesis of moreacid-stable derivatives, for example, roxithromycin, clarithromycin, andthe 15-membered ring macrolide azithromycin.

However, all these drugs, including 16-membered ring macrolides, presentseveral drawbacks. They are inactive against MLSB-resistant streptococci(MLSB=Macrolides-Lincosamides-type B Streptogramines) and with theexception of azithromycin, weakly active against Haemophilus influenzae.Futhermore, the resistance of Streptococcus pneumoniae to erythromycinhas increased significantly in recent years (5% to above 40%). There isa high percentage of cross-resistance to penicillin among theseisolates, with a worldwide epidemic spread of 10-40% in some areas.

There is, therefore, a clear need for new macrolides that overcome theproblem of pneumococcal resistance, have good pharmacokinetic propertiesand acid stability while continuing to be active against H. influenzae.These new macrolides will be ideal candidates for drug development inthe first line therapy of upper respiratory tract infections (“URTI”)and lower respiratory tract infections (“LRTI”).

Kashimura et al. have disclosed 6-O-methylerythromycin derivativeshaving a tricyclic basic nuclear structure in European Application559896, published Nov. 11, 1991. Also, Asaka et al. have disclosed5-O-desoaminylerythronolide derivatives containing a tricyclic carbamatestructure in PCT Application WO 93/21200, published Apr. 22, 1992.

Recently erythromycin derivatives containing a variety of substituentsat the 6-O position have been disclosed in U.S. Pat. Nos. 5,866,549 and6,075,011 as well as PCT Application WO 00/78773. Furthermore, Ma et al.have described erythromycin derivatives with aryl groups tethered to theC-6 position in J. Med Chem., 44, pp 4137-4156 (2001). PCT applicationWO 97/10251, published Mar. 20, 1997, discloses intermediates useful forpreparation of 6-O-methyl 3-descladinose erythromycin derivatives. U.S.Pat. Nos. 5,866,549 and 6,075,011, and PCT application WO 00/78773,published Dec. 28, 2000, disclose certain 6-O-substituted erythromycinderivatives.

PCT Application WO 03/095466 A1, published Nov. 20, 2003 and PCTApplication WO 03/097659 Al, published Nov. 27, 2003 disclose a seriesof bicyclic erythromycin derivatives.

SUMMARY OF THE INVENTION

The present invention provides a novel class of C3-C6 bridgederythromycin compounds that possess antibacterial activity.

The compounds of the present invention are represented by formula (I) asillustrated below:

or the pharmaceutically acceptable salts, esters and prodrugs thereof,

-   wherein R₁ is selected from the group consisting of:    -   a) hydrogen; deuterium;    -   b) methyl;    -   c) allyl;    -   d) —CH₂OH;    -   e) aryl; substituted aryl;    -   f) heteroaryl; substituted heteroaryl;    -   g) —C₁-C₆ alkyl, —C₂-C₆ alkenyl, or —C₂-C₆ alkynyl containing 0,        1, 2, or 3 heteroatoms selected from O, S or N, optionally        substituted with one or more substituents selected from halogen,        aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

R₂ is selected from the group consisting of:

-   -   -   a) hydrogen;

    -   b) hydroxy;

    -   c) activated hydroxy;

-   when R₁ is H, R₂ is selected from the group consisting of:    -   a) hydrogen;    -   b) hydroxy;    -   c) activated hydroxy;    -   d) N₃;    -   e) NH₂;    -   f) CN;    -   g) protected hydroxy;    -   h) protected amino;    -   i) -A-R₃, where A is O, O(CO)O, S, S(O), SO₂, NH, NCH₃, NH(CO),        NH(CO)O, NH(CO)NH or NHSO₂; and R₃ is independently selected        from the group consisting of:        -   (i) hydrogen;        -   (ii) aryl; substituted aryl; heteroaryl; substituted            heteroaryl;        -   (iii) —C₁-C₆ alkyl, —C₂-C₆ alkenyl, or —C₂-C₆ alkynyl            containing 0, 1, 2, or 3 heteroatoms selected from O, S or            N, optionally substituted with one or more substituents            selected from halogen, aryl, substituted aryl, heteroaryl,            or substituted heteroaryl;    -    provided that when A=S(O) or SO₂, R₃ cannot be hydrogen;    -   (j)    -    wherein E is absent, O, S, S(O), S(O)₂, NR₃, N(CO)R₃, NSO₂R₃,        or CHR₃; n=1, 2, or 3; and m=2 or 3, where R₃ is as previously        defined;

-   alternatively, R₁ and R₂ taken together with the carbon atom to    which they are attached is:    -   a) C═O;    -   b) C(OR₄)(OR₅), where R₄ and R₅ are selected from the group        consisting of C₁-C₁₂ alkyl, aryl or substituted aryl; or taken        together are —(CH₂)_(m)—, and where m is 2 or 3;    -   c) C(SR₄)(SR₅), where R₄ and R₅ are as previously defined above;    -   d) C═CHR₃, where R₃ is as previously defined;    -   e) C═CNH(amino protecting group)    -   f) C═N-Z-R₃, where Z is absent, O, NH, NH(CO), NH(CO)NH or        NHSO₂, and R₃ is as previously defined;

-   X and Y are:    -   a) when one of X and Y is a hydrogen, the other is selected        from:        -   (i) hydrogen;        -   (ii) hydroxy;        -   (iii) activated hydroxy;        -   (iv) N₃;        -   (v) NH₂;        -   (vi) CN;        -   (vii) protected hydroxy;        -   (viii) protected amino;        -   (ix) -A-R₃, where A is O, O(CO)O, S, S(O), SO₂, NH, NCH₃,            NH(CO), NH(CO)O, NH(CO)NH or NHSO₂, where R₃ is as            previously defined;        -   (x)        -    wherein E is absent, O, S, S(O), S(O)₂, NR₃, N(CO)R₃,            NSO₂R₃, or CHR₃; n=1, 2, or 3; and m=2 or 3, where R₃ is as            previously defined;    -   b) X, Y taken together with the carbon atom to which they are        attached is:        -   (i) C═O;        -   (ii) C═N—OR₆, wherein R₆ is selected from the group            consisting of:            -   1. hydrogen;            -   2. —CH₂O(CH₂)₂OCH₃;            -   3. —CH₂O(CH₂O)_(n)CH₃, wherein n is as previously                defined;            -   4. —C₁-C₁₂ alkyl , containing 0, 1, 2, or 3 heteroatoms,                optionally substituted with one or more substituents                selected from the group consisting of halogen, aryl,                substituted aryl, heteroaryl and substituted heteroaryl;            -   5. C₃-C₁₂ cycloalkyl;            -   6. C(O)—C₁-C₁₂ alkyl;            -   7. C(O)—(C₃-C₁₂ cycloalkyl);            -   8. C(O)—R₃, wherein R₃ is as previously defined; and            -   9. —Si(R_(a))(R_(b))(R_(c)), wherein R_(a), R_(b) and                R_(c) are each independently selected from the group                consisting of C₁-C₁₂ alkyl, aryl and substituted aryl;        -   (iii) C═N—O—C(R₇)(R₈)—O—R₉, wherein R₇ and R₈ taken together            with the carbon atom to which they are attached form a C₃ to            C₁₂ cycloalkyl group or each independently is selected from            the group consisting of: hydrogen and C₁-C₁₂ alkyl; and R₉            is selected from the group consisting of:            -   1. —C₁-C₁₂ alkyl, optionally substituted with one or                more substituents selected from the group consisting of                halogen, aryl, substituted aryl, heteroaryl and                substituted heteroaryl;            -   2. —C₃-C₁₂ cycloalkyl; and            -   3. —Si(R_(a))(R_(b))(R_(c)), wherein R_(a), R_(b) and                R_(c) are as previously defined;

-   B is NR₃₀R₄₀; wherein R₃₀ and R₄₀ is independently selected from the    group consisting of hydrogen, acyl, a substituted or unsubstituted,    saturated or unsaturated aliphatic group, a substituted or    unsubstituted, saturated or unsaturated alicyclic group, a    substituted or unsubstituted aromatic group, a substituted or    unsubstituted heteroaromatic group, saturated or unsaturated    heterocyclic group; or can be taken together with the nitrogen atom    to which they are attached to form a substituted or unsubstituted    heterocyclic or heteroaromatic ring; preferably B is N(CH₃)₂;

-   V is selected from the group consisting of hydrogen, azido, cyano,    nitro, aldehyde, carboxylic acid, amide, a substituted or    unsubstituted, saturated or unsaturated aliphatic group; preferably    V is CH₃;

-   Q is selected from the group consisting of:    -   (a) hydrogen;    -   (b) protected hydroxy;    -   (c) OR₂₁, where R₂₁ is selected from the group consisting of:        -   (i) hydrogen;        -   (ii) aryl; substituted aryl; heteroaryl; substituted            heteroaryl;        -   (iii) —C₁-C₆ alkyl, —C₂-C₆ alkenyl, or —C₂-C₆ alkynyl            containing 0, 1, 2, or 3 heteroatoms selected from O, S or            N, optionally substituted with one or more substituents            selected from halogen, aryl, substituted aryl, heteroaryl,            or substituted heteroaryl;        -   (iv) —C₃-C₁₂ cycloalkyl containing 0, 1, 2, or 3 heteroatoms            selected from O, S or N, optionally substituted with one or            more substituents selected from halogen, aryl, substituted            aryl, heteroaryl, or substituted heteroaryl;

-   L is selected from the group consisting of:    -   (a) —CH₂CH₃;    -   (b) —CH(OH)CH₃;    -   (c) —C₁-C₆ alkyl, —C₂-C₆ alkenyl, or —C₂-C₆ alkynyl optionally        substituted with one or more substituents selected from the        group consisting of aryl, substituted aryl, heteroaryl, and        substituted heteroaryl;

-   Rx is hydrogen, hydroxy protecting group or hydroxy prodrug group.

In another embodiment of the present invention there are disclosedpharmaceutical compositions comprising a therapeutically effectiveamount of a compound of the invention in combination with apharmaceutically acceptable carrier or excipient. In yet anotherembodiment of the invention are methods of treating antibacterialinfections in a subject in need of such treatment with saidpharmaceutical compositions. Suitable carriers and formulations of thecompounds of the present invention are disclosed.

DETAILED DESCRIPTION OF THE INVENTION

In a first embodiment of the compounds of the present invention arecompounds represented by formula I as illustrated above, or apharmaceutically acceptable salt, ester or prodrug thereof.

In a second embodiment of the compounds of the present invention arecompounds represented by formula II as illustrated below, or apharmaceutically acceptable salt, ester or prodrug thereof:

where R₁, R₂ and R_(x) are as previously defined.

In a third embodiment of the compounds of the present invention arecompounds represented by formula III as illustrated below, or apharmaceutically acceptable salt, ester or prodrug thereof:

where R₁, R₂ and R_(x), are as previously defined.

In a fourth embodiment of the compounds of the present invention arecompounds represented by formula IV as illustrated below, or apharmaceutically acceptable salt, ester or prodrug thereof:

where R₁, R₂ and R_(x) are as previously defined.

In a fifth embodiment of the compounds of the present invention arecompounds represented by formula V as illustrated below, or apharmaceutically acceptable salt, ester or prodrug thereof:

where R₁, R₂ and R_(x) are as previously defined.

In a sixth embodiment of the compounds of the present invention arecompounds represented by formula VI as illustrated below, or apharmaceutically acceptable salt, ester or prodrug thereof:

where R₁, R₂ and R_(x) are as previously defined.

Representative compounds according to the invention are those selectedfrom the group consisting of:

-   (1) Compound of formula II wherein R₁ and R₂ taken together with the    carbon atom to which they are attached are C═CH₂, and Rx=Ac.-   (2) Compound of formula IV wherein R₁ and R₂ taken together with the    carbon atom to which they are attached are C═CH₂, and Rx=Ac.-   (3) Compound of formula II wherein R₁ and R₂ taken together with the    carbon atom to which they are attached are C═CH₂, and Rx=H.-   (4) Compound of formula IV wherein R₁ and R₂ taken together with the    carbon atom to which they are attached are C═CH₂, and Rx=H.-   (5) Compound of formula III wherein R₁ and R₂ taken together with    the carbon atom to which they are attached are C═CH₂, and Rx=H.-   (6) Compound of formula III wherein R₁ and R₂ taken together with    the carbon atom to which they are attached are    C═NO[6′-Amino-[2,2′]bipyridinyl-6-ylmethyl], and Rx=H.-   (7) Compound of formula V wherein R₁ and R₂ taken together with the    carbon atom to which they are attached are    C═NO[6′-Amino-[2,2′]bipyridinyl-6-ylmethyl], and Rx=H.

Further representative species of the present invention are:

Compounds (8)-(14) of the formula A:

wherein X and Y taken together with the carbon to which they areattached (CXY) and Rx are delineated for each example in TABLE 1: TABLE1 Compound CXY Rx (8) C═NOAc Ac (9) C═NOH H (10) C═NH H (11) CH(NH₂) H(12) CH(OH) H (13) C═O H (14) C═O Ac

Further representative species of the present invention are:

Compounds (15)-(272) of the formula (III):

wherein R₁ and R₂ taken together with the carbon to which they areattached (CR₁R₂) and Rx are delineated for each example in Table 2.TABLE 2 Compound CR₁R₂ Rx (15) C═NO[CH₂Ph] Ac (16) C═NO[CH₂Ph] H (17)C═NO[(CH₂)₂Ph] Ac (18) C═NO[(CH₂)₂Ph] H (19) C═NO[(CH₂)₃Ph] Ac (20)C═NO[(CH₂)₃Ph] H (21) C═NO[(CH₂)₄Ph] Ac (22) C═NO[(CH₂)₄Ph] H (23)C═NO[Ph] Ac (24) C═NO[Ph] H (25) C═NO[(CH₂)₅Ph] Ac (26) C═NO[(CH₂)₅Ph] H(27)

Ac (28)

H (29)

Ac (30)

H (31)

Ac (32)

H (33)

Ac (34)

H (35)

Ac (36)

H (37) C═NNH[Ph] Ac (38) C═NNH[Ph] H (39) C═CH[CH═CHPh] Ac (40)CH(CH₂)₃Ph H (41) CHCH₃ H (42) CHOH Ac (43) CHOH H (44)

Ac (45)

H (46)

Ac (47)

H (48)

Ac (49)

H (50)

Ac (51)

H (52)

Ac (53)

H (54)

Ac (55)

H (56)

Ac (57)

H (58) C═NO[Ph] Ac (59) C═NO[Ph] H (60) C═CH₂ H (61) C═CH₂ H (62)

Ac (63)

H (64)

Ac (65)

H (66)

Ac (67)

H (68)

Ac (69)

H (70)

Ac (71)

H (72)

Ac (73)

H (74)

Ac (75)

H (76)

Ac (77)

H (78)

Ac (79)

H (80)

Ac (81)

H (82)

Ac (83)

H (84)

Ac (85)

H (86)

Ac (87)

H (88)

Ac (89)

H (90)

Ac (91)

H (92)

Ac (93)

H (94)

Ac (95)

H (96)

Ac (97)

H (98)

Ac (99)

H (100)

Ac (101)

H (102)

Ac (103)

H (104)

Ac (105)

H (106)

Ac (107)

H (108)

Ac (109)

H (110)

Ac (111)

H (112)

Ac (113)

H (114) C═N—OH Ac (115) C═N—OH H (116)

Ac (117)

H (118)

Ac (119)

H (120)

Ac (121)

H (122)

Ac (123)

H (124)

Ac (125)

H (126)

Ac (127)

H (128)

Ac (129)

H (130)

Ac (131)

H (132)

Ac (133)

H (134)

Ac (135)

H (136)

Ac (137)

H (138)

Ac (139)

H (140)

Ac (141)

H (142)

Ac (143)

H (144)

Ac (145)

H (146)

Ac (147)

H (148)

Ac (149)

H (150)

Ac (151)

H (152)

Ac (153)

H (154)

Ac (155)

H (156)

Ac (157)

H (158)

H (159)

Ac (160)

H (161)

Ac (162)

H (163)

Ac (164)

H (165)

H (166)

Ac (167)

H (168)

Ac (169)

H (170)

Ac (171)

H (172)

Ac (173)

H (174)

Ac (175)

H (176)

Ac (177)

H (178)

Ac (179)

H (180)

Ac (181)

H (182)

H (183)

Ac (184)

H (185)

Ac (186)

H (187)

Ac (188)

H (189)

Ac (190)

H (191)

Ac (192)

H (193)

Ac (194)

H (195)

Ac (196)

H (197)

Ac (198)

H (199)

H (200)

Ac (201)

H (202)

Ac (203)

H (204)

Ac (205)

H (206)

Ac (207)

H (208)

Ac (209)

H (210)

Ac (211)

H (212)

Ac (213)

H (214)

Ac (215)

H (216)

Ac (217)

H (218)

Ac (219)

H (220)

Ac (221)

H (222)

Ac (223)

H (224)

Ac (225)

H (226)

Ac (227)

H (228)

Ac (229)

H (230)

Ac (231)

H (232)

Ac (233)

H (234)

Ac (235)

H (236)

Ac (237)

H (238)

Ac (239)

H (240)

Ac (241)

H (242)

Ac (243)

H (244)

Ac (245)

H (246)

Ac (247)

H (248)

H (249)

Ac (250)

H (251)

Ac (252)

H (253)

Ac (254)

H (255)

Ac (256)

H (257)

Ac (258)

H (259)

Ac (260)

H (261)

Ac (262)

H (263)

Ac (264)

H (265)

Ac (266)

H (267)

Ac (268)

H (269)

Ac (270)

H (271)

Ac (272)

H

Further representative species of the present invention are:

wherein R₃ is delineated for each example in Table 4. TABLE 4 CompoundR₃ (273)

(274)

(275)

(276)

(277)

(278)

(279)

(280)

(281)

(282)

(283)

(284)

(285)

(286)

(287)

(288)

(289)

(290)

(291)

(292)

(293)

(294)

(295)

(296)

(297)

(298)

(299)

(300)

(301)

(302)

(303)

(304)

(305)

(306)

(307)

(308)

(309)

(310)

(311)

(312)

(313)

(314)

(315)

(316)

(317)

(318)

(319)

(320)

(321)

(322)

(323)

(324)

(325)

(326)

(327)

(328)

(329)

(330)

(331)

(332)

(333)

(334)

(335)

(336)

(337)

(338)

(339)

(340)

(341)

(342)

(343)

(344)

(345)

(346)

(347)

(348)

(349)

(350)

(351)

(352)

(353)

(354)

(355)

(356)

(357)

(358)

(359)

(360)

(361)

(362)

(363)

(364)

(365)

(366)

(367)

(368)

(369)

(370)

(371)

(372)

(373)

(374)

(375)

(376)

(377)

(378)

(379)

(380)

(381)

(382)

(383)

(384)

(385)

(386)

(387)

(388)

(389)

(390)

(391)

(392)

(393)

(394)

(395)

(396)

(397)

(398)

(399)

(400)

(401)

(402)

(403)

(404)

(405)

(406)

(407)

(408)

(409)

(410)

(411)

(412)

(413)

(414)

(415)

(416)

(417)

(418)

(419)

(420)

(421)

(422)

(423)

(424)

(425)

(426)

(427)

(428)

(429)

(430)

(431)

(432)

(433)

(434)

A further embodiment of the present invention includes pharmaceuticalcompositions comprising any single compound delineated herein, or apharmaceutically acceptable salt, ester, or prodrug thereof, with apharmaceutically acceptable carrier or excipient.

Yet another embodiment of the present invention is a pharmaceuticalcomposition comprising a combination of two or more compounds delineatedherein, or a pharmaceutically acceptable salt, ester, or prodrugthereof, with a pharmaceutically acceptable carrier or excipient.

Yet a further embodiment of the present invention is a pharmaceuticalcomposition comprising any single compound delineated herein incombination with one or more antibiotics known in the art, or apharmaceutically acceptable salt, ester, or prodrug thereof, with apharmaceutically acceptable carrier or excipient.

In addition, the present invention contemplates processes of making anycompound delineated herein via any synthetic method delineated herein.

Definitions

Listed below are definitions of various terms used to describe thisinvention.

These definitions apply to the terms as they are used throughout thisspecification and claims, unless otherwise limited in specificinstances, either individually or as part of a larger group.

The term “aryl,” as used herein, refers to a mono- or polycycliccarbocyclic ring system having one or two aromatic rings including, butnot limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, idenyland the like.

The term “heteroaryl,” as used herein, refers to a mono- or polycyclic(e.g. bi-, or tri-cyclic or more) aromatic radical or ring having fromfive to ten ring atoms of which one or more ring atom is selected from,for example, S, O and N; zero, one or two ring atoms are additionalheteroatoms independently selected from, for example, S, O and N; andthe remaining ring atoms are carbon, wherein any N or S contained withinthe ring may be optionally oxidized. Heteroaryl includes, but is notlimited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl,imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl,thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl,benzooxazolyl, quinoxalinyl, and the like.

In accordance with the invention, any of the aryls, substituted aryls,heteroaryls and substituted heteroaryls described herein, can be anyaromatic group. Aromatic groups can be substituted or unsubstituted.

The terms “C₁-C₆ alkyl,” or “C₁-C₁₂ alkyl,” as used herein, refer tosaturated, straight- or branched-chain hydrocarbon radicals containingbetween one and six, or one and twelve carbon atoms, respectively.Examples of C₁-C₆ alkyl radicals include, but are not limited to,methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl andn-hexyl radicals; and examples of C₁-C₁₂ alkyl radicals include, but arenot limited to, ethyl, propyl, isopropyl, n-hexyl, octyl, decyl, dodecylradicals.

The term “C₂-C₆ alkenyl,” as used herein, denotes a monovalent groupderived from a hydrocarbon moiety containing from two to six carbonatoms having at least one carbon-carbon double bond by the removal of asingle hydrogen atom. Alkenyl groups include, but are not limited to,for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and thelike.

The term “C₂-C₆ alkynyl,” as used herein, denotes a monovalent groupderived from a hydrocarbon moiety containing from two to six carbonatoms having at least one carbon-carbon triple bond by the removal of asingle hydrogen atom. Representative alkenyl groups include, but are notlimited to, for example, ethynyl, 1-propynyl, 1-butynyl, and the like.

The term “C₃-C₁₂-cycloalkyl,” as used herein, denotes a monovalent groupderived from a monocyclic or polycyclic saturated carbocyclic ringcompound by the removal of a single hydrogen atom. Examples include, butnot limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,bicyclo[2.2.1]heptyl, and bicyclo[2.2.2]octyl.

It is understood that any alkyl, alkenyl, alkynyl and cycloalkyl moietydescribed herein can also be an aliphatic group, an alicyclic group or aheterocyclic group. An “aliphatic group” is non-aromatic moiety that maycontain any combination of carbon atoms, hydrogen atoms, halogen atoms,oxygen, nitrogen or other atoms, and optionally contain one or moreunits of unsaturation, e.g., double and/or triple bonds. An aliphaticgroup may be straight chained, branched or cyclic and preferablycontains between about 1 and about 24 carbon atoms, more typicallybetween about 1 and about 12 carbon atoms. In addition to aliphatichydrocarbon groups, aliphatic groups include, for example,polyalkoxyalkyls, such as polyalkylene glycols, polyamines, andpolyimines, for example. Such aliphatic groups may be furthersubstituted.

The term “alicyclic,” as used herein, denotes a monovalent group derivedfrom a monocyclic or bicyclic saturated carbocyclic ring compound by theremoval of a single hydrogen atom. Examples include, but not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl,and bicyclo[2.2.2]octyl. Such alicyclic groups may be furthersubstituted.

The term “heterocyclic” as used herein, refers to a non-aromatic 5-, 6-or 7-membered ring or a bi- or tri-cyclic group fused system, where (i)each ring contains between one and three heteroatoms independentlyselected from oxygen, sulfur and nitrogen, (ii) each 5-membered ring has0 to 1 double bonds and each 6-membered ring has 0 to 2 double bonds,(iii) the nitrogen and sulfur heteroatoms may optionally be oxidized,(iv) the nitrogen heteroatom may optionally be quaternized, (iv) any ofthe above rings may be fused to a benzene ring, and (v) the remainingring atoms are carbon atoms which may be optionally oxo-substituted.Representative heterocycloalkyl groups include, but are not limited to,[1,3]dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl,imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl,morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl,pyridazinonyl, and tetrahydrofuryl. Such heterocyclic groups may befurther substituted.

The terms “substituted aryl”, “substituted heteroaryl,” “substitutedC₁-C₆ alkyl,” or “substituted C₁-C₁₂ alkyl,” “substituted C₂-C₆alkenyl,” “substituted C₂-C₆ alkynyl,” “substituted C₁-C₈ alkylene,”“substituted C₂-C₈ alkenylene,” “substituted C₂-C₈ alkynylene,”“substituted aliphatic,” as used herein, refer to aryl, heteroaryl,C₁-C₆ alkyl, C₁-C₁₂ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₈ alkylene,C₂-C₈ alkenylene, substituted C₂-C₈ alkynylene, aliphatic groups aspreviously defined, substituted by independent replacement of one, two,or three or more of the hydrogen atoms thereon with substituentsincluding, but not limited to, —F, —Cl, —Br, —I, —OH, protectedhydroxyl, —NO₂, —CN, —C₁-C₁₂-alkyl optionally substituted with, forexample, halogen, C₂-C₁₂-alkenyl optionally substituted with, forexample, halogen, —C₂-C₁₂-alkynyl optionally substituted with, forexample, halogen, —NH₂, protected amino, —NH—C₁-C₁₂-alkyl,—NH—C₂-C₁₂-alkenyl, —NH—C₂-C₁₂-alkenyl, —NH—C₃-C₁₂-cycloalkyl, —NH-aryl,—NH-heteroaryl, —NH-heterocycloalkyl, -dialkylamino, -diarylamino,-diheteroarylamino, —O—C₁-C₁₂-alkyl, —O—C₂-C₁₂-alkenyl,—O—C₂-C₁₂-alkenyl, —O—C₃-C₁₂-cycloalkyl, —O-aryl, —O-heteroaryl,—O-heterocycloalkyl, —C(O)—C₁-C₁₂-alkyl, —C(O)—C₂-C₁₂-alkenyl,—C(O)—C₂-C₁₂-alkenyl, —C(O)—C₃-C₁₂-cycloalkyl, —C(O)-aryl,—C(O)-heteroaryl, —C(O)-heterocycloalkyl, —CONH₂, —CONH—C₁-C₁₂-alkyl,—CONH—C₂-C₁₂-alkenyl, —CONH—C₂-C₁₂-alkenyl, —CONH—C₃-C₁₂-cycloalkyl,—CONH-aryl, —CONH-heteroaryl, —CONH-heterocycloalkyl,—OCO₂—C₁-C₁₂-alkyl, —OCO₂—C₂-C₁₂-alkenyl, —OCO₂—C₂-C₁₂-alkenyl,—OCO₂—C₃-C₁₂-cycloalkyl, —OCO₂-aryl, —OCO₂-heteroaryl,—OCO₂-heterocycloalkyl, —OCONH₂, —OCONH—C₁-C₁₂-alkyl,—OCONH—C₂-C₁₂-alkenyl, —OCONH—C₂-C₁₂-alkenyl, —OCONH—C₃-C₁₂-cycloalkyl,—OCONH-aryl, —OCONH-heteroaryl, —OCONH-heterocycloalkyl,—NHC(O)—C₁-C₁₂-alkyl, —NHC(O)—C₂-C₁₂-alkenyl, —NHC(O)—C₂-C₁₂-alkenyl,—NHC(O)—C₃-C₁₂-cycloalkyl, —NHC(O)-aryl, —NHC(O)-heteroaryl,—NHC(O)-heterocycloalkyl, —NHCO₂—C₁-C₁₂-alkyl, —NHCO₂—C₂-C₁₂-alkenyl,—NHCO₂—C₂-C₁₂-alkenyl, —NHCO₂—C₃-C₁₂-cycloalkyl, —NHCO₂-aryl,—NHCO₂-heteroaryl, —NHCO₂-heterocycloalkyl, —NHC(O)NH₂,—NHC(O)NH—C₁-C₁₂-alkyl, —NHC(O)NH—C₂-C₁₂-alkenyl,—NHC(O)NH—C₂-C₁₂-alkenyl, —NHC(O)NH—C₃-C₁₂-cycloalkyl, —NHC(O)NH-aryl,—NHC(O)NH-heteroaryl, —NHC(O)NH-heterocycloalkyl, NHC(S)NH₂,—NHC(S)NH—C₁-C₁₂-alkyl, —NHC(S)NH—C₂-C₁₂-alkenyl,—NHC(S)NH—C₂-C₁₂-alkenyl, —NHC(S)NH—C₃-C₁₂-cycloalkyl, —NHC(S)NH-aryl,—NHC(S)NH-heteroaryl, —NHC(S)NH-heterocycloalkyl, —NHC(H)NH₂,—NHC(NH)NH-C₁-C₁₂-alkyl, —NHC(M)NH—C₂-C₁₂-alkenyl,—NHC(NH)NH—C₂-C₁₂-alkenyl, —NHC(NH)NH—C₃-C₁₂-cycloalkyl,—NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl, —NHC(NH)NH-heterocycloalkyl,—NHC(NH)-C₁-C₁₂-alkyl, —NHC(NH)—C₂-C₁₂-alkenyl, —NHC(NH)—C₂-C₁₂-alkenyl,—NHC(NH)—C₃-C₁₂-cycloalkyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl,—NHC(NH)-heterocycloalkyl, —C(NH)NH—C₁-C₁₂-alkyl,—C(NH)NH—C₂-C₁₂-alkenyl, —C(NH)NH—C₂-C₁₂-alkenyl,—C(NH)NH—C₃-C₁₂-cycloalkyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl,—C(NH)NH-heterocycloalkyl, —S(O)—C₁-C₁₂-alkyl, —S(O)—C₂-C₁₂-alkenyl,—S(O)—C₂-C₁₂-alkenyl, —S(O)—C₃-C₁₂-cycloalkyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)-heterocycloalkyl-SO₂NH₂, —SO₂NH—C₁-C₁₂-alkyl,—SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₃-C₁₂-cycloalkyl,—SO₂NH-aryl, —SO₂NH-heteroaryl, —SO₂NH-heterocycloalkyl,—NHSO₂—C₁-C₁₂-alkyl, —NHSO₂—C₂-C₁₂-alkenyl, —NHSO₂—C₂-C₁₂-alkenyl,—NHSO₂—C₃-C₁₂-cycloalkyl, —NHSO₂-aryl, —NHSO₂-heteroaryl,—NHSO₂-heterocycloalkyl, —CH₂NH₂, —CH₂SO₂CH₃, -aryl, -arylalkyl,-heteroaryl, -heteroarylalkyl, -heterocycloalkyl, —C₃-C₁₂-cycloalkyl,polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, —SH,—S-C₁-C₁₂-alkyl, —S—C₂-C₁₂-alkenyl, —S—C₂-C₁₂-alkenyl,—S—C₃-C₁₂-cycloalkyl, —S-aryl, —S-heteroaryl, —S-heterocycloalkyl, ormethylthiomethyl. It is understood that the aryls, heteroaryls, alkyls,and the like can be further substituted.

The term “halogen,” as used herein, refers to an atom selected fromfluorine, chlorine, bromine and iodine.

The term “hydroxy activating group”, as used herein, refers to a labilechemical moiety which is known in the art to activate a hydroxyl groupso that it will depart during synthetic procedures such as in asubstitution or an elimination reactions. Examples of hydroxylactivating group include, but not limited to, mesylate, tosylate,triflate, p-nitrobenzoate, phosphonate and the like.

The term “activated hydroxy”, as used herein, refers to a hydroxy groupactivated with a hydroxyl activating group, as defined above, includingmesylate, tosylate, triflate, p-nitrobenzoate, phosphonate groups, forexample.

The term “hydroxy protecting group,” as used herein, refers to a labilechemical moiety which is known in the art to protect a hydroxyl groupagainst undesired reactions during synthetic procedures. After saidsynthetic procedure(s) the hydroxy protecting group as described hereinmay be selectively removed. Hydroxy protecting groups as known in theare described generally in T. H. Greene and P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York(1999). Examples of hydroxyl protecting groups includebenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl,4-methoxybenzyloxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl,isopropoxycarbonyl, diphenylmethoxycarbonyl,2,2,2-trichloroethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl,2-furfuryloxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl,trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t-butyl,2,2,2-trichloroethyl, 2-trimethylsilyl ethyl, 1,1-dimethyl-2-propenyl,3-methyl-3-butenyl, allyl, benzyl, para-methoxybenzyldiphenylmethyl,triphenylmethyl(trityl), tetrahydrofuryl, methoxymethyl,methylthiomethyl, benzyloxymethyl, 2,2,2-triehloroethoxymethyl,2-(trimethylsilyl)ethoxymethyl, methanesulfonyl, para-toluenesulfonyl,trimethylsilyl, triethylsilyl, triisopropylsilyl, and the like.Preferred hydroxyl protecting groups for the present invention areacetyl (Ac or —C(O)CH₃), benzoyl (Bz or —C(O)C₆H₅), and trimethylsilyl(TMS or-Si(CH₃)₃).

The term “protected hydroxy,” as used herein, refers to a hydroxy groupprotected with a hydroxy protecting group, as defined above, includingbenzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups,for example.

The term “hydroxy prodrug group”, as used herein, refers to a promoietygroup which is known in the art to change the physicochemical, and hencethe biological properties of a parent drug in a transient manner bycovering or masking the hydroxy group. After said syntheticprocedure(s), the hydroxy prodrug group as described herein must becapable of reverting back to hydroxy group in vivo. Hydroxy prodruggroups as known in the art are described generally In Kenneth B. Sloan,Prodrugs, Topical and Ocular Drug Delivery, (Drugs and thePharmaceutical Sciences; Volume 53), Marcel Dekker, Inc., New York(1992).

The term “amino protecting group,” as used herein, refers to a labilechemical moiety which is known in the art to protect an amino groupagainst undesired reactions during synthetic procedures. After saidsynthetic procedure(s) the amino protecting group as described hereinmay be selectively removed. Amino protecting groups as known in the aredescribed generally In T. H. Greene and P. G. M. Wuts, Protective Groupsin Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999).Examples of amino protecting groups include, but are not limited to,t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyloxycarbonyl, and thelike.

The term “protected amino,” as used herein, refers to an amino groupprotected with an amino protecting group as defined above.

The term “aprotic solvent,” as used herein, refers to a solvent that isrelatively inert to proton activity, i.e., not acting as a proton-donor.Examples include, but are not limited to, hydrocarbons, such as hexaneand toluene, for example, halogenated hydrocarbons, such as, forexample, methylene chloride, ethylene chloride, chloroform, and thelike, heterocyclic compounds, such as, for example, tetrahydrofuran andN-methylpyrrolidinone, and ethers such as diethyl ether,bis-methoxymethyl ether. Such compounds are well known to those skilledin the art, and it will be obvious to those skilled in the art thatindividual solvents or mixtures thereof may be preferred for specificcompounds and reaction conditions, depending upon such factors as thesolubility of reagents, reactivity of reagents and preferred temperatureranges, for example. Further discussions of aprotic solvents may befound in organic chemistry textbooks or in specialized monographs, forexample: Organic Solvents Physical Properties and Methods ofPurification, 4th ed., edited by John A. Riddick et al., Vol. II, in theTechniques of Chemistry Series, John Wiley & Sons, NY, 1986.

The term “protogenic organic solvent,” as used herein, refers to asolvent that tends to provide protons, such as an alcohol, for example,methanol, ethanol, propanol, isopropanol, butanol, t-butanol, and thelike. Such solvents are well known to those skilled in the art, and itwill be obvious to those skilled in the art that individual solvents ormixtures thereof may be preferred for specific compounds and reactionconditions, depending upon such factors as the solubility of reagents,reactivity of reagents and preferred temperature ranges, for example.Further discussions of protogenic solvents may be found in organicchemistry textbooks or in specialized monographs, for example: OrganicSolvents Physical Properties and Methods of Purification, 4th ed.,edited by John A. Riddick et al., Vol. II, in the Techniques ofChemistry Series, John Wiley & Sons, NY, 1986.

Combinations of substituents and variables envisioned by this inventionare only those that result in the formation of stable compounds. Theterm “stable”, as used herein, refers to compounds which possessstability sufficient to allow manufacture and which maintains theintegrity of the compound for a sufficient period of time to be usefulfor the purposes detailed herein (e.g., therapeutic or prophylacticadministration to a subject).

The synthesized compounds can be separated from a reaction mixture andfurther purified by a method such as column chromatography, highpressure liquid chromatography, or recrystallization. As can beappreciated by the skilled artisan, further methods of synthesizing thecompounds of the formulae herein will be evident to those of ordinaryskill in the art. Additionally, the various synthetic steps may beperformed in an alternate sequence or order to give the desiredcompounds. Synthetic chemistry transformations and protecting groupmethodologies (protection and deprotection) useful in synthesizing thecompounds described herein are known in the art and include, forexample, those such as described In R. Larock, Comprehensive OrganicTransformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons(1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents forOrganic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed.,Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons(1995), and subsequent editions thereof.

The term “subject” as used herein refers to an animal. Preferably theanimal is a mammal. More preferably the mammal is a human. A subjectalso refers to, for example, dogs, cats, horses, cows, pigs, guineapigs, fish, birds and the like.

The compounds of this invention may be modified by appending appropriatefunctionalities to enhance selective biological properties. Suchmodifications are known in the art and may include those which increasebiological penetration into a given biological system (e.g., blood,lymphatic system, central nervous system), increase oral availability,increase solubility to allow administration by injection, altermetabolism and alter rate of excretion.

The compounds described herein contain one or more asymmetric centersand thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)— or (S)—, or as (D)- or (L)- for amino acids.The present invention is meant to include all such possible isomers, aswell as their racemic and optically pure forms. Optical isomers may beprepared from their respective optically active precursors by theprocedures described above, or by resolving the racemic mixtures. Theresolution can be carried out in the presence of a resolving agent, bychromatography or by repeated crystallization or by some combination ofthese techniques which are known to those skilled in the art. Furtherdetails regarding resolutions can be found in Jacques, et al.,Enantiomers Racemates, and Resolutions (John Wiley & Sons, 1981). Whenthe compounds described herein contain olefinic double bonds, otherunsaturation, or other centers of geometric asymmetry, and unlessspecified otherwise, it is intended that the compounds include both Eand Z geometric isomers or cis- and trans-isomers. Likewise, alltautomeric forms are also intended to be included. The configuration ofany carbon-carbon double bond appearing herein is selected forconvenience only and is not intended to designate a particularconfiguration unless the text so states; thus a carbon-carbon doublebond or carbon-heteroatom double bond depicted arbitrarily herein astrans may be cis, trans, or a mixture of the two in any proportion.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge, etal. describes pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared insitu during the final isolation and purification of the compounds of theinvention, or separately by reacting the free base function with asuitable organic acid. Examples of pharmaceutically acceptable include,but are not limited to, nontoxic acid addition salts are salts of anamino group formed with inorganic acids such as hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid orwith organic acids such as acetic acid, maleic acid, tartaric acid,citric acid, succinic acid or malonic acid or by using other methodsused in the art such as ion exchange. Other pharmaceutically acceptablesalts include, but are not limited to, adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like. Representative alkali or alkaline earth metal saltsinclude sodium, lithium, potassium, calcium, magnesium, and the like.Further pharmaceutically acceptable salts include, when appropriate,nontoxic ammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and arylsulfonate.

As used herein, the term “pharmaceutically acceptable ester” refers toesters which hydrolyze in vivo and include those that break down readilyin the human body to leave the parent compound or a salt thereof.Suitable ester groups include, for example, those derived frompharmaceutically acceptable aliphatic carboxylic acids, particularlyalkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which eachalkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.Examples of particular esters include, but are not limited to, formates,acetates, propionates, butyrates, acrylates and ethylsuccinates.

The term “pharmaceutically acceptable prodrugs” as used herein refers tothose prodrugs of the compounds of the present invention which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of humans and lower animals with undue toxicity,irritation, allergic response, and the like, commensurate with areasonable benefit/risk ratio, and effective for their intended use, aswell as the zwitterionic forms, where possible, of the compounds of thepresent invention. “Prodrug”, as used herein means a compound which isconvertible in vivo by metabolic means (e.g. by hydrolysis) to acompound of Formula I. Various forms of prodrugs are known in the art,for example, as discussed in Bundgaard, (ed.), Design of Prodrugs,Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4,Academic Press (1985); Krogsgaard-Larsen, et al., (ed). “Design andApplication of Prodrugs, Textbook of Drug Design and Development,Chapter 5, 113-191 (1991); Bundgaard, et al., Journal of Drug DeliverReviews, 8:1-38(1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285et seq. (1988); Higuchi and Stella (eds.) Prodrugs as Novel DrugDelivery Systems, American Chemical Society (1975); and Bernard Testa &Joachim Mayer, “Hydrolysis In Drug And Prodrug Metabolism: Chemistry,Biochemistry And Enzymology,” John Wiley and Sons, Ltd. (2002).

This invention also encompasses pharmaceutical compositions containing,and methods of treating bacterial infections through administering,pharmaceutically acceptable prodrugs of compounds of the formula I. Forexample, compounds of formula I having free amino, amido, hydroxy orcarboxylic groups can be converted into prodrugs. Prodrugs includecompounds wherein an amino acid residue, or a polypeptide chain of twoor more (e.g., two, three or four) amino acid residues is covalentlyjoined through an amide or ester bond to a free amino, hydroxy orcarboxylic acid group of compounds of formula I. The amino acid residuesinclude but are not limited to the 20 naturally occurring amino acidscommonly designated by three letter symbols and also includes4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,citrulline, homocysteine, homoserine, omithine and methionine sulfone.Additional types of prodrugs are also encompassed. For instance, freecarboxyl groups can be derivatized as amides or alkyl esters. Freehydroxy groups may be derivatized using groups including but not limitedto hemisuccinates, phosphate esters, dimethylaminoacetates, andphosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug DeliveryReviews, 1996, 19, 115. Carbamate prodrugs of hydroxy and amino groupsare also included, as are carbonate prodrugs, sulfonate esters andsulfate esters of hydroxy groups. Derivatization of hydroxy groups as(acyloxy)methyl and (acyloxy)ethyl ethers wherein the acyl group may bean alkyl ester, optionally substituted with groups including but notlimited to ether, amine and carboxylic acid functionalities, or wherethe acyl group is an amino acid ester as described above, are alsoencompassed. Prodrugs of this type are described in J. Med. Chem. 1996,39, 10. Free amines can also be derivatized as amides, sulfonamides orphosphonamides. All of these prodrug moieties may incorporate groupsincluding but not limited to ether, amine and carboxylic acidfunctionalities.

As used herein, unless otherwise indicated, the term “bacterialinfection(s)” or “protozoa infections”; includes, but is not limited to,bacterial infections and protozoa infections that occur in mammals, fishand birds as well as disorders related to bacterial infections andprotozoa infections that may be treated or prevented by administeringantibiotics such as the compounds of the present invention. Suchbacterial infections and protozoa infections and disorders related tosuch infections include, but are not limited to, the following:pneumonia, otitis media, sinusitus, bronchitis, tonsillitis, cysticfibrosis and mastoiditis related to infection by Streptococcuspneumoniae, Haemophilus influenzae, Moraxella catarrhalis,Staphylococcus aureus, Peptostreptococcus spp, or Pseudomonas spp.;pharynigitis, rheumatic fever, and glomerulonephritis related toinfection by Streptococcus pyogenes, Groups C and G streptococci,Clostridium diptheriae, or Actinobacillus haemolyticum; respiratorytract infections related to infection by Mycoplasma pneumoniae,Legionella pneumophila, Streptococcus pneumoniae, Haemophilusinfluenzae, or Chlamydia pneumoniae; uncomplicated skin and soft tissueinfections, abscesses and osteomyelitis, and puerperal fever related toinfection by Staphylococcus aureus, coagulase-positive staphylococci(i.e., S. epidermidis, S. hemolyticus, etc.), S. pyogenes, S.agalactiae, Streptococcal groups C-F (minute-colony streptococci),viridans streptococci, Corynebacterium spp., Clostridium spp., orBartonella henselae; uncomplicated acute urinary tract infectionsrelated to infection by S. saprophyticus or Enterococcus spp.;urethritis and cervicitis; and sexually transmitted diseases related toinfection by Chlamydia trachomatis, Haemophilus ducreyi, Treponemapallidum, Ureaplasma urealyticum, or Nesseria gonorrheae; toxin diseasesrelated to infection by S. aureus (food poisoning and Toxic shocksyndrome), or Groups A, S. and C streptococci; ulcers related toinfection by Helicobacter pylori; systemic febrile syndromes related toinfection by Borrelia recurrentis; Lyme disease related to infection byBorrelia burgdorferi; conjunctivitis, keratitis, and dacrocystitisrelated to infection by C. trachomatis, N. gonorrhoeae, S. aureus, S.pneumoniae, S. pyogenes, H. influenzae, or Listeria spp.; disseminatedMycobacterium avium complex (MAC) disease related to infection byMycobacterium avium, or Mycobacterium intracellulare; gastroenteritisrelated to infection by Campylobacter jejuni; intestinal protozoarelated to infection by Cryptosporidium spp. odontogenic infectionrelated to infection by viridans streptococci; persistent cough relatedto infection by Bordetella pertussis; gas gangrene related to infectionby Clostridium perfringens or Bacteroides spp.; Skin infection by S.aureus, Propionibacterium acne; atherosclerosis related to infection byHelicobacter pylori or Chlamydia pneumoniae; or the like.

Bacterial infections and protozoa infections and disorders related tosuch infections that may be treated or prevented in animals include, butare not limited to, the following: bovine respiratory disease related toinfection by P. haemolytica., P. multocida, Mycoplasma bovis, orBordetella spp.; cow enteric disease related to infection by E. coli orprotozoa (i.e., coccidia, cryptosporidia, etc.), dairy cow mastitisrelated to infection by S. aureus, S. uberis, S. agalactiae, S.dysgalactiae, Klebsiella spp., Corynebacterium, or Enterococcus spp.;swine respiratory disease related to infection by A. pleuropneumoniae.,P. multocida, or Mycoplasma spp.; swine enteric disease related toinfection by E. coli, Lawsonia intracellularis, Salmonella spp., orSerpulina hyodyisinteriae; cow footrot related to infection byFusobacterium spp.; cow metritis related to infection by E. coli; cowhairy warts related to Infection by Fusobacterium necrophorum orBacteroides nodosus; cow pink-eye related to infection by Moraxellabovis, cow premature abortion related to infection by protozoa (i.e.neosporium); urinary tract infection in dogs and cats related toinfection by E. coli; skin and soft tissue infections in dogs and catsrelated to infection by S. epidermidis, S. intermedius, coagulase neg.Staphylococcus or P. multocida; and dental or mouth infections in dogsand oats related to infection by Alcaligenes spp., Bacteroides spp.,Clostridium spp., Enterobacter spp., Eubacterium spp.,Peptostreptococcus spp., Porphfyromonas spp., Campylobacter spp.,Actinomyces spp., Erysipelothrix spp., Rhodococcus spp., Trypanosomaspp., Plasmodium spp., Babesia spp., Toxoplasma spp., Pneumocystis spp.,Leishmania spp., and Trichomonas spp. or Prevotella spp. Other bacterialinfections and protozoa infections and disorders related to suchinfections that may be treated or prevented in accord with the method ofthe present invention are referred to in J. P. Sanford et al., “TheSanford Guide To Antimicrobial Therapy,” 26th Edition, (AntimicrobialTherapy, Inc., 1996).

Antibacterial Activity

25 Susceptibility tests can be used to quantitatively measure the invitro activity of an antimicrobial agent against a given bacterialisolate. Compounds are tested for in vitro antibacterial activity by amicro-dilution method. Minimal Inhibitory Concentration (MIC) isdetermined in 96 well microtiter plates utilizing the appropriateMueller Hinton Broth medium (CAMHB) for the observed bacterial isolates.Antimicrobial agents are serially diluted (2-fold) in DMSO to produce aconcentration range from about 64 μg/ml to about 0.03 μg/ml. The dilutedcompounds (2 μl/well) are then transferred into sterile, uninoculatedCAMHB (0.2 mL) by use of a 96 fixed tip-pipetting station. The inoculumfor each bacterial strain is standardized to 5×10⁵ CFU/mL by opticalcomparison to a 0.5 McFarland turbidity standard. The plates areinoculated with 10 μl/well of adjusted bacterial inoculum. The 96 wellplates are covered and incubated at 35±2° C. for 24 hours in ambient airenvironment. Following incubation, plate wells are visually examined byOptical Density measurement for the presence of growth (turbidity). Thelowest concentration of an antimicrobial agent at which no visiblegrowth occurs is defined as the MIC. The compounds of the inventiongenerally demonstrated an MIC in the range from about 64 μg/ml to about0.03 μg/ml.

All in vitro testing follows the guidelines described in the ApprovedStandards M7-A4 protocol, published by the National Committee forClinical Laboratory Standards (NCCLS).

The invention further provides compositions and methods of treatingpatients suffering from an inflammatory condition comprisingadministering to a patient in need thereof, a therapeutically effectiveamount of at least one compound of Formulas of the invention. Specificexamples of inflammatory conditions treatable according to the inventioninclude, but are not limited to, scleritis; epi-scleritis; allergicconjunctivitis; pulmonary inflammatory diseases, particularly CF,asthma, chronic obstructive pulmonary disease (COPD), allergicbronchopulmonary aspergillosis (ABPA), and sarcoidosis;procto-sigmoiditis; allergic rhinitis; arthritis; tendonitis; apthousstomatitis; and inflammatory bowel disease.

The invention further provides compositions and methods for i)prophylactic treatment of those patients susceptible to the symptoms CFincluding pulmonary infection and inflammation associated with CF, ii)treatment at the initial onset of symptoms of pulmonary infection andinflammation associated with CF, and iii) treatment of ongoing orrelapsing symptoms of infection and inflammation associated with CF. Inaccordance with the invention a compound according to any one offormulas of the invention, is administered to a patient in need oftreatment for CF, in amount sufficient to prevent, diminish or eradicatesymptoms of CF including chronic pulmonary inflammation and infection.

Pharmaceutical Compositions

The pharmaceutical compositions of the present invention comprise atherapeutically effective amount of a compound of the present inventionformulated together with one or more pharmaceutically acceptablecarriers or excipients.

As used herein, the term “pharmaceutically acceptable carrier orexcipient” means a non-toxic, inert solid, semi-solid or liquid filler,diluent, encapsulating material or formulation auxiliary of any type.Some examples of materials which can serve as pharmaceuticallyacceptable carriers are sugars such as lactose, glucose and sucrose;starches such as corn starch and potato starch; cellulose and itsderivatives such as sodium carboxymethyl cellulose, ethyl cellulose andcellulose acetate; powdered tragacanth; malt; gelatin; talc; excipientssuch as cocoa butter and suppository waxes; oils such as peanut oil,cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; glycols such as propylene glycol; esters such as ethyloleate and ethyl laurate; agar; buffering agents such as magnesiumhydroxide and aluminun hydroxide; alginic acid; pyrogen-free water;isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffersolutions, as well as other non-toxic compatible lubricants such assodium lauryl sulfate and magnesium stearate, as well as coloringagents, releasing agents, coating agents, sweetening, flavoring andperfuming agents, preservatives and antioxidants can also be present inthe composition, according to the judgment of the formulator.

The pharmaceutical compositions of this invention may be administeredorally, parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir, preferably by oraladministration or administration by injection. The pharmaceuticalcompositions of this invention may contain any conventional non-toxicpharmaceutically-acceptable carriers, adjuvants or vehicles. In somecases, the pH of the formulation may be adjusted with pharmaceuticallyacceptable acids, bases or buffers to enhance the stability of theformulated compound or its delivery form. The term parenteral as usedherein includes subcutaneous, intracutaneous, intravenous,intramuscular, intraarticular, intraarterial, intrasynovial,intrasternal, intrathecal, intralesional and intracranial injection orinfusion techniques.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsmay contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurftiryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions, may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolution,which, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle. Injectable depot forms are made by forming microencapsulematrices of the drug in biodegradable polymers such aspolylactide-polyglycolide. Depending upon the ratio of drug to polymerand the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions that are compatible with body tissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or: a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, eye ointments, powders and solutionsare also contemplated as being within the scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants suchas chlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlleddelivery of a compound to the body. Such dosage forms can be made bydissolving or dispensing the compound in the proper medium. Absorptionenhancers can also be used to increase the flux of the compound acrossthe skin. The rate can be controlled by either providing a ratecontrolling membrane or by dispersing the compound in a polymer matrixor gel.

For pulmonary delivery, a therapeutic composition of the invention isformulated and administered to the patient in solid or liquidparticulate form by direct administration e.g., inhalation into therespiratory system. Solid or liquid particulate forms of the activecompound prepared for practicing the present invention include particlesof respirable size: that is, particles of a size sufficiently small topass through the mouth and larynx upon inhalation and into the bronchiand alveoli of the lungs.

Delivery of aerosolized therapeutics, particularly aerosolizedantibiotics, is known in the art (see, for example U.S. Pat. No.5,767,068 to VanDevanter et al., U.S. Pat. No. 5,508,269 to Smith etal., and WO 98/43,650 by Montgomery, all of which are incorporatedherein by reference). A discussion of pulmonary delivery of antibioticsis also found in U.S. Pat. No. 6,014,969, incorporated herein byreference.

According to the methods of treatment of the present invention,bacterial infections, cystic fibrosis and inflammatory conditions aretreated or prevented in a patient such as a human or another animal byadministering to the patient a therapeutically effective amount of acompound of the invention, in such amounts and for such time as isnecessary to achieve the desired result.

By a “therapeutically effective amount” of a compound of the inventionis meant an amount of the compound which confers a therapeutic effect onthe treated subject, at a reasonable benefit/risk ratio applicable toany medical treatment. The therapeutic effect may be objective (i.e.,measurable by some test or marker) or subjective (i.e., subject gives anindication of or feels an effect). An effective amount of the compounddescribed above may range from about 0.1 mg/Kg to about 500 mg/Kg,preferably from about 1 to about 50 mg/Kg. Effective doses will alsovary depending on route of administration, as well as the possibility ofco-usage with other agents. It will be understood, however, that thetotal daily usage of the compounds and compositions of the presentinvention will be decided by the attending physician within the scope ofsound medical judgment. The specific therapeutically effective doselevel for any particular patient will depend upon a variety of factorsincluding the disorder being treated and the severity of the disorder;the activity of the specific compound employed; the specific compositionemployed; the age, body weight, general health, sex and diet of thepatient; the time of administration, route of administration, and rateof excretion of the specific compound employed; the duration of thetreatment; drugs used in combination or contemporaneously with thespecific compound employed; and like factors well known in the medicalarts.

The total daily dose of the compounds of this invention administered toa human or other animal in single or in divided doses can be in amounts,for example, from 0.01 to 50 mg/kg body weight or more usually from 0.1to 25 mg/kg body weight. Single dose compositions may contain suchamounts or submultiples thereof to make up the daily dose. In general,treatment regimens according to the present invention compriseadministration to a patient in need of such treatment from about 10 mgto about 1000 mg of the compound(s) of this invention per day in singleor multiple doses.

The compounds of the formulae described herein can, for example, beadministered by injection, intravenously, intraarterially, subdermally,intraperitoneally, intramuscularly, or subcutaneously; or orally,buccally, nasally, transmucosally, topically, in an ophthalmicpreparation, or by inhalation, with a dosage ranging from about 0.1 toabout 500 mg/kg of body weight, alternatively dosages between 1 mg and1000 mg/dose, every 4 to 120 hours, or according to the requirements ofthe particular drug. The methods herein contemplate administration of aneffective amount of compound or compound composition to achieve thedesired or stated effect. Typically, the pharmaceutical compositions ofthis invention will be administered from about 1 to about 6 times perday or alternatively, as a continuous infusion. Such administration canbe used as a chronic or acute therapy. The amount of active ingredientthat may be combined with pharmaceutically exipients or carriers toproduce a single dosage form will vary depending upon the host treatedand the particular mode of administration. A typical preparation willcontain from about 5% to about 95% active compound (w/w). Alternatively,such preparations may contain from about 20% to about 80% activecompound.

Lower or higher doses than those recited above may be required. Specificdosage and treatment regimens for any particular patient will dependupon a variety of factors, including the activity of the specificcompound employed, the age, body weight, general health status, sex,diet, time of administration, rate of excretion, drug combination, theseverity and course of the disease, condition or symptoms, the patient'sdisposition to the disease, condition or symptoms, and the judgment ofthe treating physician.

Upon improvement of a patient's condition, a maintenance dose of acompound, composition or combination of this invention may beadministered, if necessary. Subsequently, the dosage or frequency ofadministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained when the symptomshave been alleviated to the desired level. Patients may, however,require intermittent treatment on a long-term basis upon any recurrenceof disease symptoms.

When the compositions of this invention comprise a combination of acompound of the formulae described herein and one or more additionaltherapeutic or prophylactic agents, both the compound and the additionalagent should be present at dosage levels of between about 1 to 100%, andmore preferably between about 5 to 95% of the dosage normallyadministered in a monotherapy regimen. The additional agents may beadministered separately, as part of a multiple dose regimen, from thecompounds of this invention. Alternatively, those agents may be part ofa single dosage form, mixed together with the compounds of thisinvention in a single composition.

The pharmaceutical compositions of this invention can be administeredorally to fish by blending said pharmaceutical compositions into fishfeed or said pharmaceutical compositions may be dissolved in water inwhich infected fish are placed, a method commonly referred to as amedicated bath. The dosage for the treatment of fish differs dependingupon the purpose of administration (prevention or cure of disease) andtype of administration, size and extent of infection of the fish to betreated. Generally, a dosage of 5-1000 mg, preferably 20-100 mg, per kgof body weight of fish may be administered per day, either at one timeor divided into several times. It will be recognized that theabove-specified dosage is only a general range which may be reduced orincreased depending upon the age, body weight, condition of disease,etc. of the fish.

Unless otherwise defined, all technical and scientific terms used hereinare accorded the meaning commonly known to one of ordinary skill in theart. All publications, patents, published patent applications, and otherreferences mentioned herein are hereby incorporated by reference intheir entirety.

Abbreviations

Abbreviations which may be used in the descriptions of the scheme andthe examples that follow are:

Ac for acetyl;

AIBN for azobisisobutyronitrile;

Bu₃SnH for tributyltin hydride;

CDI for carbonyldiimidazole;

dba for dibenzylidene acetone;

dppb for diphenylphosphino butane;

DBU for 1,8-diazabicyclo[5.4.0]undec-7-ene;

DEAD for diethylazodicarboxylate;

DMAP for dimethylaminopyridine;

DMF for dimethyl formamide;

DPPA for diphenylphosphoryl azide;

EtOAc for ethyl acetate;

MeOH for methanol;

Ms for mesylate or O—SO₂—CF₃;

NaN(TMS)₂ for sodium bis(trimethylsilyl)amide;

NMMO for N-methylmorpholine N-oxide;

TEA for triethylamine;

THF for tetrahydrofuran;

TPP or PPh₃ for triphenylphosphine;

MOM for methoxymethyl;

Boc for t-butoxycarbonyl;

Bz for benzoyl;

Bn for benzyl;

Ph for phenyl;

POPd for dihydrogendichlorobis(di-tert-butylphosphinito-OP)palladate(II);

TBS for tert-butyl dimethylsilyl; or

TMS for trimethylsilyl.

Synthetic Methods

The compounds and processes of the present invention will be betterunderstood in connection with the following synthetic schemes thatillustrate the methods by which the compounds of the invention may beprepared.

A process of the invention, as illustrated in Scheme 1, involvespreparing a compound of formula (1-5) by reacting a compound of formula(1-3) with a suitable alkylating agent.

In accordance with Scheme 1, the 9-keto group of erythromycins can beinitially converted into an oxime by methods described in U.S. Pat. No.4,990,602, followed by removal of the cladinose moiety of the macrolideof formula (1-1) either by mild acid hydrolysis or by enzymatichydrolysis to afford compounds of formula (1-2). Representative acidsinclude, but are not limited to, dilute hydrochloric acid, sulfuricacid, perchloric acid, chloroacetic acid, dichloroacetic acid ortrifluoroacetic acid. Suitable solvents for the reaction include, butare not limited to, methanol, ethanol, isopropanol, butanol, water andmixtures there of. Reaction times are typically 0.5 to 24 hours. Thereaction temperature is preferably 0-80° C.

The 2′-hydroxyl and the oxime groups are protected by reaction withsuitable hydroxyl protecting reagents. Typical hydroxyl protectingreagents include, but are not limited to, acetylating agents, silylatingagents, acid anhydrides, and the like. A more thorough discussion ofsolvents and conditions for protecting the hydroxyl group can be foundin T. W. Greene and P. G. M. Wuts, Protective Groups in OrganicSynthesis, 3^(rd) ed., John Wiley & Son, Inc, 1999. Acetylation of thehydroxyl group is typically accomplished by treating the compound (1-2)with an acetylating reagent such as acetic anhydride to give compound offormula (1-3).

The erythromycin derivative of formula (1-3) is then reacted with analkylating agent of the formula:

wherein R₃ is as previously defined and R₁₀ is —C₁-C₁₂ alkyl, —C₁-C₁₂alkenyl, or —C₁-C₁₂ alkynyl optionally substituted with one or moresubstitutents selected from halogen, aryl, substituted aryl, heteroaryl,or substituted heteroaryl; —C₃-C₁₂ cycloalkyl.

Most palladium (0) catalysts are expected to work in this process. Somepalladium (II) catalysts, such as palladium (II) acetate, which isconverted into a palladium (0) species in-situ by the actions of aphosphine, will work as well. See, for example, Beller et al. Angew.Chem. Int. Ed. Engl., 1995, 34 (17), 1848. The palladium catalyst can beselected from, but not limited to, palladium (II) acetate,tetrakis(triphenylphospine)palladium (0),tris(dibenzylideneacetone)dipalladium,tetradibenzylideneacetone)dipalladium and the like. Palladium on carbonand palladium (II) halide catalysts are less preferred than otherpalladium catalysts for this process.

Suitable phosphines include, but are not limited to, triphenylphosphine,bis(diphenylphosphino)methane, bis(diphenylphosphino)ethane,bis(diphenylphosphino)propane, 1,4-bis(diphenylphosphino)butane,bis(diphenylphosphino)pentane, and tri-o-tolyl-phosphine, and the like.The reaction is carried out in an aprotic solvent, preferably atelevated temperature, preferably at or above 50° C. Suitable aproticsolvents include, but are not limited to, tetrahydrofuran,N,N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone,toluene, hexamethylphosphoric triamide, 1,2-dimethoxyethane,methyl-tert-butyl ether, heptane, acetonitrile, isopropyl acetate andethyl acetate.

Generally, the alkylating agents have the formula (1-4) as previouslydescribed. The preferred alkylating agents are those wherein R₁₀ istert-butyl, isopropyl or isobutyl. The alkylating reagents are preparedby reaction of a diol with a wide variety of compounds for incorporatingthe di-carbonate moiety. The compounds include, but are not limited to,tert-butyl chloroformate, di-tert-butyl dicarbonate, and1-(tert-butoxycarbonyl)imidazole and the reaction is carried out in thepresence of an organic or an inorganic base. The temperature of thereaction varies from about −30° C. to approximately 30° C.

An alternative method of converting the alcohol into the carbonateinvolves treating the alcohol with phosgene or triphosgene to preparethe chloroformate derivative of the diol. The di-chloroformatederivative is then converted into the di-carbonate by the methodsdescribed in Cotarca, L., Delogu, P., Nardelli, A., Sunijic, V,Synthesis, 1996, 553. The reaction can be carried out in a variety oforganic solvents such as dichloromethane, toluene, diethyl ether, ethylacetate and chloroform in the presence of a base. Examples of suitablebases include, but are not limited to, sodium hydroxide, potassiumhydroxide, ammonium hydroxide, sodium carbonate, potassium carbonate,ammonium carbonate, DMAP, pyridine, triethylamine and the like. Thetemperature can vary from 0° C. to approximately 60° C. The reactionruns to completion in 3 to 5 hours.

Scheme 2 outlined the synthesis of intermediate (2-3). Selectivedeprotection of the oxime is typically accomplished via alkalinehydrolysis in protic solvents. Representative alkali include lithiumhydroxide, sodium hydroxide, potassium hydroxide, and the like. Solventswhich are applicable include but are not limited to tetrahydrofuran,1,4-dioxane, 1,2-dimethoxyethane, isopropanol, ethanol, butanol, waterand mixtures thereof. The reaction temperature is preferably 0° to 35°C. and reaction time is preferably 0.5 to 24 hours.

In a like fashion, simultaneous deprotection of both the oxime and the2′ hydroxyl can be accomplished under a variey of conditions. Conditionsfor deprotection include, but are not limited to, treating with analcoholic solvent at from room temperature to reflux, or treatment witha primary amine, such as butylamine. Alcoholic solvents preferred forthe deprotection are methanol and ethanol. A more thorough discussion ofthe procedures, reagents and conditions for removing protecting groupsis described in the literature, for example, by T. W. Greene and P. G.M. Wuts In “Protective Groups in Organic Synthesis” 3^(rd) ed., JohnWiley & Son, Inc, 1999, referred to above herein.

Deoxygenation of compounds of formula (2-1) under reducing conditionsgives the resulting imine followed by hydrolysis by aqueous alcohol atelevated temperature to give compounds of formula (2-2). Many reducingagents can be used to effect this transformation including, but notlimited to: lithium aluminum hydride, titanium trichloride, sodiumnitrite, sodium thiosulfate, sodium cyanoborohydride, borane, andvarious sulfides such as sodium hydrogen sulfide, sodium ethoxide. For amore detailed account of oxime reduction see J. March in “AdvancedOrganic Chemistry” 4^(th) ed., Wiley & Son, Inc, 1992, which isincorporated by reference herein.

A particularly useful method for the reduction of oximes to thecorresponding imine uses a sulfite reducing agent, such as sodiumnitrite, sodium hydrogensulfite or titanium trichloride under acidicconditions, typically in protic solvents. Representative acids include,but are not limited to, acetic acid, formic acid, dilute hydrochloricacid, dilute phosphoric acid, dilute sulfuric acid, and the like. Proticsolvents include, but are not limited to, mixtures of water andmethanol, ethanol, isopropanol, or butanol. The reaction is typicallycarried out at 25° to 110° C., preferably for between 1 and 10 hours.

Oxidation of compound of formula (2-2) with oxidant such as but notlimited to, Jones reagent, Collins' reagent, Corey's reagent, pyridiniumdichromate, postassium permanganate, manganese dioxide, and rutheniumtetroxide, provides dehydrated 9-12 oxolides (2-3) and hydroxyl9,12-oxolides (2-4). For a more detailed account of alcohol oxidation,see J. March in “Advanced Organic Chemistry” 4^(th) ed., Wiley & Son,Inc, 1992, which is incorporated by reference herein.

Scheme 3 shows another process of the invention by which to preparecompound of the present invention. Selective hydrogenation of the enonedouble bond of compounds (2-3) into the corresponding oxolides (3-1) canbe accomplished by treating compounds (2-3) with reducing agents such asbut not limited to DIBAL, Hydrogen and a Rh catalyst, Bu₃SnH—Pd(Ph₃)₄,or postassium triphenylborohydride. Preferably, the reducing agent isDIBAL at low temperature.

Scheme 4 illustrates another process of the invention by which toprepare compound of the present invention. Conversion of alkenes (3-1)into ketones (4-1) can be accomplished by ozonolysis followed bydecomposition of the ozonide with the appropriate reducing agents. Thereaction is typically carried out in an inert solvent such as, but notlimited to, methanol, ethanol, ethyl acetate, glacial acetic acid,chloroform, methylene chloride or hexane or mixtures thereof, preferablymethanol, preferably at −78° C. to −20° C. Representative reducingagents are, for example, triphenylphosphine, trimethylphosphite,thiourea, and dimethyl sulfide, preferably triphenylphosphine. A morethorough discussion of ozonolysis and conditions therefor may be foundIn J. March, Advanced Organic Chemistry, 4^(th) ed., Wiley & Son, Inc,1992. Alternatively, compounds of formula (4-1) can be prepared fromcompounds of formula (3-1) via dihydroxydation with OSO₄ followed byNaIO₄ cleavage.

Compounds according to the invention of the formula (4-1) can be furtherfunctionalized in a variety of ways. Scheme 5 details a procedure forthe conversion of the ketone of formula (4-1) into an oxime of formula(5-1). Oxime formation can be accomplished using the appropriatesubstituted hydroxylamine under either acidic or basic conditions in avariety of solvents. Representative acids include, but are not limitedto, hydrochloric, phosphoric, sulfuric, p-toluenesulfonic, andpyridinium p-toluene sulfonate. Likewise, representative bases include,but are not limited to, triethylamine, pyridine, diisopropylphenylamine, 2,6-lutidine, and the like. Appropriate solvents include, but arenot limited to, methanol, ethanol, water, tetrahydrofuran,1,2-dimethoxyethane, and ethyl acetate. Preferably the reaction iscarried out in ethanol using triethylamine as the base. The reactiontemperature is generally 25° C. and reaction time is 1 to 12 hours.

It will be appreciated by one skilled in the art that ketones of formula(4-1) can be transformed into alkenes of formula (5-2) and (5-7) viaWittig reaction with the appropriate phosphonium salt in the presence ofa base, see (a) Burke, Tetrahedron Lett., 1987, 4143-4146, (b) Rathkeand Nowak, J. Org. Chem., 1985, 2624-2626, (c) Maryanoff and Reitz,Chem. Rev., 1989, 863-927. Furthermore, vinyl halides of formula (5-7)can be functionalized by Sonogashira coupling with alkynes in thepresence of a palladium catalyst, a copper halide and an amine base togive compounds of formula (5-8) (see (a) Sonogashira, ComprehensiveOrganic Synthesis, Volume 3, Chapters 2,4; (b) Sonogashira, Synthesis1977, 777.). In a similar manner, alkenes of formula (5-2) can beobtained from vinyl halides (5-7) via Suzuki cross coupling withorganoboron reagents in the presence of a palladium catalyst and a base,or via Stille cross coupling with organostananes in the presence of apalladium catalyst (see (a) Suzuki, J. Organomet. Chem. 1999,576,147-168, (b) Stille, Angew. Chem. Int. Ed. Engl., 1986, 508-524 (c)Farina, J. Am. Chem. Soc., 1991, 9585-9595).

Furthermore, alcohols of type (5-3) can be prepared by reduction of thecorresponding ketone of formula (4-1) under a variety of conditions (seeHudlicky, M. Reductions in Organic Chemistry, Ellis Horwood Limited:Chichester, 1984). The alcohols thus derived can be further modified togive compounds of formula (5-4). A process to generate compounds offormula (5-4) includes, but is not limited to, alkylation of the alcoholwith an electrophile or conversion of the alcohol into a leaving group,such as a triflate, tosylate, phosphonate, halide, or the like, followedby displacement with a heteroatom nucleophile (e.g. an amine, alkoxide,sulfide or the like).

Yet another means by which to functionalize ketones of formula (4-1) isvia addition of Grignard reagents to form alcohols of formula (5-5). Therequisite Grignard reagents are readily available via the reaction of avariety of alkyl or aryl halides with magnesium under standardconditions (see B. S. Fumiss, A. J. Hannaford, P. W. G. Smith, A. R.Tatchell, Vogel's Textbook of Practical Organic Chemistry, 5^(th) ed.,Longman, 1989). The addition is performed in an inert solvent, generallyat low temperatures. Suitable solvents include, but are not limited to,tetrahydrofuran, diethylether, 1,4-dioxane, 1,2-dimethoxyethane, andhexanes. Preferably the solvent is tetrahydrofuran or diethylether.Preferably the reaction is run at −78° C. to 0° C.

In a similar way, reaction with other organometallic reagents gives riseto alcohols of formula (i-5). Examples of useful organometallic reagentsinclude, but are not limited to, organo-aluminum, organo-lithium,organo-cerium, organo-zinc, organo-thallium, and organo-boron reagents.A more thorough discussion of organometallic reagents can be found In B.S. Fumiss, A. J. Hannaford, P. W. G. Smith, A. R. Tatchell, Vogel'sTextbook of Practical Organic Chemistry 5^(th) ed., Longman, 1989.

Ketone of formula (4-1) can be further utilized by conversion into amineof formula (5-6) via a reductive amination. Reductive amination isachieved by treating the ketone with an amine in the presence of areducing agent to obtain the product amine (5-6). The reaction can becarried out either with or without added acid. Examples of acids thatare commonly used include, but are not limited to, hydrochloric,phosphoric, sulfuric, acetic, and the like. Reducing agents that effectreductive amination include, but are not limited to, hydrogen and acatalyst, zinc and hydrochloric acid, sodium cyanoborohydride, sodiumborohydride, iron pentacarbonyl, and alcoholic potassium hydroxide.Generally alcoholic solvents are used. The preferred conditions usesodium cyanoborohydride in methanol with added acetic acid.

It will be appreciated by one skilled in the art, that the unsaturatedcompounds represented by compounds (5-2) and (5-8) can be reduced toform the corresponding saturated compound (see Hudlicky, M., Reductionsin Organic Chemistry, Ellis Horwood Limited: Chichester, 1984).

Compounds of the invention according to formula (6-1) are also capableof further functionalization to generate compounds of the presentinvention. Alkene (6-1) can be treated with an aryl halide or aryltriflate in the presence of a palladium catalyst [Pd(0) or Pd(II)] toprovide compound (6-3): (See (a) Heck, Palladium Reagents in OrganicSynthesis, Academic Press: New York, 1985, Chapter 1; (b) Sonogashira,Comprehensive Organic Synthesis, Volume 3, Chapters 2,4; (c)Sonogashira, Synthesis 1977, 777). Under the Heck coupling conditions,regioisomers and stereoisomers of the double bond are possible.Alternatively, compound (6-1) can undergo a cross metathesis reactionwith vinylaromatic derivatives using ruthenium catalysts to givecompounds of formula (6-2) (see (a) J. Org Chem. 2000, 65, 2204-2207;(b) Reviews: Synlett. 1999, 2, 267; (c) Reviews: Ivin, K. J.; Mol, J.C., Olefin Metathesis and Metathesis Polymerization, 2^(nd) ed.,Academic Press: New York, 1997; (d) J. Org. Chem. 1999, 64, 4798-4816;(e) Angew. Chem., Int. Ed. Engl. 1997, 36, 2036-2056; (f) Tetrahedron1998, 54, 4413-4450).

Compounds according to the invention of the formula (7-1) can be furtherfunctionalized in a variety of ways. Scheme 7 details a procedure forthe conversion of the ketone of formula (7-1) into a hydroxyl of formula(7-2). The alcohols of type (7-2) can be prepared by reduction of thecorresponding ketone of formula (7-1) under a variety of conditions (seeHudlicky, M. Reductions in Organic Chemistry, Ellis Horwood Limited:Chichester, 1984). The alcohols thus derived can be further modified togive compounds of formula (7-5). A process to generate compounds offormula (7-5) includes, but is not limited to, alkylation of the alcoholwith an electrophile or conversion of the alcohol into a leaving group,such as a triflate, tosylate, phosphonate, halide, or the like, followedby displacement with a heteroatom nucleophile (e.g. an amine, alkoxide,sulfide or the like). Alternatively, conversion of the ketone moiety offormula 7-1 into the corresponding amino functional group of formula 7-4can be achieved via oxime intermediate 7-3.

All references cited herein, whether in print, electronic, computerreadable storage media or other form, are expressly incorporated byreference in their entirety, including but not limited to, abstracts,articles, journals, publications, texts, treatises, internet web sites,databases, patents, and patent publications.

EXAMPLES

The compounds and processes of the present invention will be betterunderstood in connection with the following examples, which are intendedas an illustration only and not limiting of the scope of the invention.Various changes and modifications to the disclosed embodiments will beapparent to those skilled in the art and such changes and modificationsincluding, without limitation, those relating to the chemicalstructures, substituents, derivatives, formulations and/or methods ofthe invention may be made without departing from the spirit of theinvention and the scope of the appended claims.

Example 1 Compound of Formula II wherein R₁ and R₂ Taken Together withthe Carbon Atom to which They are Attached are C═CH₂, and Rx=Ac

Step 1a.

To a flask containing a solution of commercially available Ery A oxime(1 eq.) in MeOH was slowly bubbled in anhydrous HCl gas (3.1 eq.) at 20to 30° C. for 2 hrs. After HCl gas bubbling stops, the reaction mixturewas stirred for 1 hr at room temperature. The mixture was thenconcentrated to about half the volume, and then quenched with dilute HClsolution. The resulting solution is extracted 4 times withdichloromethane. The aqueous solution is then basified with aqueouspotassium carbonate solution until pH 9.5 to 10. The mixture isextracted 4 times with dichloromethane. The combine organic extractswere washed once with water, and then evaporated to dryness. The productwas carried directly for the next step without further purification.

MS (ESI): m/z=591 [M+H].

Step 1b.

A solution of the compound from step (1a) in THF (12 L) was concentratedto a remaining volume about 9 L to azeotropically dry the materialbefore acetylation reaction. To this clear THF solution is chargedtriethylamine (3.0 eq.), and then slowly charged Ac₂O (2.3 eq.) at20-30° C. over the period of about 30 min. Upon the completion of theaddition, the reaction mixture was agitated at 25° C. for additional 3hours. The reaction was diluted with EtOAc, subsequently washed 4 timeswith saturated aqueous NaHCO₃ solution, and 4 times with water. Theorganic solution is evaporated to dryness to afford the desired crudeproduct which was purified by crystallization with EtOAc/Hex.

MS (ESI): m/z=675 [M+H].

Step 1c.

To a cloudy solution of compound from step (1b) in tolulene was addedcarbonic acid 2-tert-butoxycarbonyloxymethyl-allyl ester tert-butylester (1.6 eq.) (prepared according to patent WO 03/097659 A1). Theresulting mixture was degassed 3 times at 33° C. before Pd₂(dba)₃ (4 mol%) and dppb (8 mol %) were added and the resulting mixture was heated toreflux for 5 hours. After this time, the reaction was cooled back toroom temperature and was concentrated under vacuo. The residue waspassed through a short silica gel column eluting with 100% EtOAc to 95:5(EtOAc:acetone) to give and the eluted product was concentrated andcrystallized out from EtOAc to give the desired target.

MS (ESI): m/z 627.37 [M+H].

¹³C NMR (CDCl₃, ppm) δ: 176.8, 171.3, 170.2, 168.0, 143.0, 118.9, 102.3,81.0, 80.0, 77.6, 75.0, 74.4, 72.3, 71.9, 70.6, 69.2, 63.55, 63.47,60.6, 43.6, 42.7, 40.9, 37.9, 34.9, 31.0, 28.5, 22.9, 22.1, 21.6, 21.3,21.2, 20.0, 18.9, 16.9, 15.1, 14.4, 12.2, 10.6, 10.5.

Step 1d.

A suspension of compound from step (1c) in methanol and was heated toreflux for 2.5 hours. The mixture was then cooled and evaporated todryness. The white solid residue was carried directly for the next stepwithout further purification.

MS (ESI): m/z 643.33 [M+H].

¹³C NMR (CDCl₃, ppm) δ: 177.3, 170.2, 144.7, 116.9, 104.5, 81.2, 81.0,75.6, 75.0, 72.6, 71.2, 70.9, 69.6, 66.0, 64.2, 43.8, 42.8, 40.5, 38.3,33.8, 28.8, 25.8, 22.7, 22.0, 30 21.4, 19.2, 16.6, 15.0, 12.1, 10.9,10.8.

Step 1e.

To a stirred solution of compound from step 1d (22 mmol) in ethanol wasslowly added water (75 ml). To this mixture was added NaNO₂ (5 eq.) inone portion and then it was slowly treated with 1N aqueous HCl (110 ml).The reaction temperature was warmed to 70° C. over 20 min and wasallowed to stir at this temperature for 2 hours. After the solution wascooled back to room temperature, it was basified with saturated NaHCO₃to a pH of 9-10 and then extracted 5 times with dichloromethane. Thecombined organic extracts were washed once with brine, dried over MgSO₄,filtered and concentrated. The residue was purified by crystallizationto afford the desired product.

MS (ESI): m/z 628.09 [M+H].

¹³C NMR (CDCl₃, ppm) δ: 220.6, 177.0, 143.9, 118.3, 104.5, 81.4, 80.7,75.3, 75.1, 72.6, 70.8, 69.70, 69.66, 66.0, 63.7, 45.2, 43.7, 42.7,40.5, 38.8, 38.5, 28.6, 22.7, 22.2, 21.4, 18.8, 16.6, 12.3, 12.1, 10.9,10.6.

Step 1f.

To a solution of compound from Example 9 in CH₂Cl₂ was added Ac₂O (1.2eq.). The resulting solution was stirred at room temperature for 2.5hours before it was diluted with EtOAc, washed 2 times with saturatedNaHCO₃, once with brine, dried over MgSO₄ and concentrated under vacuumto give a white solid.

MS (ESI): m/z 670.10 [M+H].

¹³C NMR (CDCl₃, ppm) δ: 220.6, 176.9, 170.1, 143.8, 118.3, 102.4, 80.8,80.5, 75.3, 75.1, 72.6, 72.0, 69.7, 69.3, 63.8, 63.5, 45.0, 43.6, 42.7,40.9, 38.7, 38.4, 30.9, 22.8, 22.2, 21.6, 21.2, 18.7, 16.9, 12.2, 12.1,10.7, 10.6.

Step 1g.

PDC (pyridiumdichromate, 0.285 g, 0.75 mmol) and potassium hydroxide(0.084 g, 1.5 mmol) were dissolved in 1.5 ml 9M H₂SO₄ aqueous solutionat 0° C. To the resulting solution was added to compound from Step 1f(0.30 g, 0.45 mmol) in CH₂Cl₂ (9.0 ml). The mixture was stirred at RTfor 45 minutes and monitored by LC-MS. The reaction was then quenchedwith saturated aqueous NaHCO₃ solution slowly to PH=10. The mixture wasextracted with CH₂Cl₂, the organic layers were combined and dried overanhydrous sodium sulfate. The organic phase was then filtered,concentrated in Vacuo and subsequently purified by silica gelchromatography (ethyl acetate: hexane/7:3 to 100% ethyl acetate) toyield the title compound (0.13 g, 45%).

MS (ESI) m/z 650.3 (M+H)⁺.

¹³C-NMR (100 MHz, CDCl₃): δ 205.4, 194.4, 177.5, 170.0, 147.6, 110.6,108.7, 103.4, 86.6, 80.8, 77.9, 74.8, 71.9, 69.4, 64.5, 63.4, 46.2,43.2, 40.9, 40.5, 31.2, 29.1, 25.6, 21.7, 21.5, 21.3, 20.3, 11.9, 11.3,11.1, 6.0.

Example 2 Compound of Formula IV wherein R₁ and R₂ Taken Together withthe Carbon Atom to which They are Attached are C═CH₂, and Rx=Ac

PDC (pyridiumdichromate, 0.285 g, 0.75 mmol) and potassium hydroxide(0.084 g, 1.5 mmol) were dissolved in 1.5 ml 9M H₂SO₄ aqueous solutionat 0° C. To the resulting solution was added to compound from Step 1f(0.30 g, 0.45 mmol) in CH₂Cl₂ (9.0 ml). The mixture was stirred at RTfor 45 minutes and monitored by LC-MS. The reaction was then quenchedwith saturated aqueous NaHCO₃ solution slowly to PH=10. The mixture wasextracted with CH₂Cl₂, the organic layers were combined and dried overanhydrous sodium sulfate. The organic phase was then filtered,concentrated in Vacuo and subsequently purified by silica gelchromatography (ethyl acetate: hexane/7:3 to 100% ethyl acetate) toyield the title compound (0.02 g, 7%).

MS (ESI) m/z 668.3 (M+H)⁺.

¹³C-NMR (100 MHz, CDCl₃, for 100-220 ppm region): δ217.2, 178.0, 170.1,148.2, 110.2, 107.4, 103.4.

Example 3 Compound of Formula II wherein R₁ and R₂ Taken Together withthe Carbon Atom to which They are Attached are C═CH₂, and Rx=H

The compound from Step 1g of Example 1 (0.13 g) was dissolved in 5 mlmethanol and stirred for 10 hours at RT to give the title compound (110mg, 90%).

MS (ESI) m/z 608.3 (M+H)⁺.

Example 4 Compound of Formula IV wherein R₁ and R₂ Taken Together withthe Carbon Atom to which They are Attached are C═CH₂, and Rx=H

The compound from Example 2 (20 mg) was dissolved in 5 ml methanol andstirred for 10 hours at RT. The solvent was removed in Vacuo and theresidue was subsequently purified by silica gel chromatography (3% 2MNH₃/MeOH in CH₂Cl₂) to yield the title compound (10 mg, 55%).

MS (ESI) m/z 626.4 (M+H)⁺.

¹³C-NMR (100 MHz, CDCl₃, for 100-220 ppm region): δ 216.8, 178.1, 148.3,110.3, 107.5, 105.2.

Example 5 Compound of Formula III wherein R₁ and R₂ Taken Together withthe Carbon Atom to which They are Attached are C═CH₂, and Rx=H

The compound from Example 3 (100 mg, 0.16 mmol) was dissolved in THF (10ml) and was cooled to −45° C. To this solution was added DIBAL (1M intoluene, 0.6 ml) in one portion. The mixture was stirred at −45° C. for3 hours and monitored by LC-MS. The reaction was then quenched with 1 mlmethanol followed by 20 ml saturated aqueous NaHCO₃ solution. Themixture was extracted with CH₂Cl₂, the organic layers were combined anddried over anhydrous sodium sulfate. The organic phase was thenfiltered, concentrated in Vacuo and subsequently purified by silica gelchromatography (3% 2M NH₃/MeOH in CH₂Cl₂) to yield the title compound(80 mg, 80%).

MS (ESI) m/z 610.4 (M+H)⁺.

¹³C-NMR (100 MHz, CDCl₃): δ 218.3, 178.3, 148.5, 109.3, 105.5, 84.8,82.4, 81.3, 80.7, 79.7, 74.8, 70.7, 69.8, 66.0, 64.0, 46.0, 43.6, 42.8,40.5, 35.4, 29.0, 28.6, 23.2, 23.1, 21.5, 20.2, 19.5, 14.6, 12.0, 11.3,10.8.

Example 6 Compound of Formula III wherein R₁ and R₂ Taken Together withthe Carbon Atom to which They are Attached areC═NO[6′-Amino-[2,2′]bipyridinyl-6-ylmethyl], and Rx=H

Step 6a. The compound from Example 5 (40 mg, 0.066 mmol), NaIO4 (31 mg,0.14 mmol) and 4% OSO₄ aqueous solution (0.04 ml, catalytic) weredissolved in acetone (2 ml) and water (2 ml). The resulting mixture wasstirred at RT for 2 hours and monitored by LC-MS. The reaction wasquenched with 15 ml water and was extracted with CH₂Cl₂, the organiclayers were combined and dried over anhydrous sodium sulfate. Theorganic phase was then filtered, concentrated in Vacuo to give the crudebridged ketone and was used directly in the next step.

MS (ESI) m/z 612.4 (M+H)⁺.

Step 6b. To a solution ofO-(6′-Amino-[2,2′]bipyridinyl-6-ylmethyl)-hydroxylamine (0.13 mmol), thecompound from step 6a (0.066 mmol) in 5 ml methanol was added 4 drops of1N HCl to PH=2. The reaction was monitored by LC-MS. The reaction wasquenched after 1 hour with 25 ml saturated aqueous NaHCO₃ solution. Themixture was extracted with CH₂Cl₂, the organic layers were combined anddried over anhydrous sodium sulfate. The organic phase was thenfiltered, concentrated in Vacuo and subsequently purified by silica gelchromatography (3% 2M NH₃/MeOH in CH₂Cl₂) to yield the title compound asa mixture of two isomers (Oxime E/Z ˜1:1, 14 mg, 30% 2-steps).

MS (ESI) m/z 810.5 (M+H)⁺.

¹³C-NMR (100 MHz, CDCl₃, for 100-220 ppm region): δ 217.8, 172.8, 157.9,138.6, 137.1, 121.0, 120.8, 119.6, 111.9, 108.8.

Example 7 Compound of Formula V wherein R₁ and R₂ Taken Together withthe Carbon Atom to which They are Attached areC═NO[6′-Amino-[2,2′]bipyridiny1-6-ylmethyl] and Rx=H

To a solution of the compound from step 6b (10 mg, 0.012 mmol) in 2 mlmethanol was added NaBH₄ (1.0 mg, 0.026 mmol). LC-MS showed completereduction in 20 minutes. The solvent was evaporated in Vacuo and theresidue was washed/ extracted with saturated aqueous NaHCO₃ solution andCH₂Cl₂. The organic layers were combined and dried over anhydrous sodiumsulfate. The organic phase was then filtered, concentrated in Vacuo andsubsequently purified by silica gel chromatography (5% 2M NH₃/MeOH inCH₂Cl₂) to yield the title compound as a mixture of two isomers (OximeE/Z˜1:1, 6.0 mg, 60%).

MS (ESI) m/z 812.5 (M+H)⁺.

¹³C-NMR (100 MHz, CDCl₃, 2 isomers, for 100-220 ppm region): δ 177.8,177.6, 160.9, 160.7, 157.9, 157.8, 155.8, 155.6, 154.8, 138.6, 137.2,137.1, 121.0, 120.9, 119.6, 119.4, 111.9, 108.8, 105.3, 105.1.

Examples 8-14 are made via similar methods delineated in Examples 1-7.

Examples 15-434 are made from the compound from Step 6a of Example 6 andthe appropriate hydroxylamine of formula R₃—O—NH₂ via similar methoddelineated in Step 6b of Example 6.

In all of the following examples a mixture of E and Z isomers arepresent which may be separated by crystallization or HPLC.

The substituted hydroxylamines used in the following examples are eithercommercially available or can be made according to PCT Application WO03/097659 A1 and US Application US 2004/0157787 A1.

1. Compounds represented by formula (I):

or the pharmaceutically acceptable salts, esters and prodrugs thereof, wherein R₁ is selected from the group consisting of: a) hydrogen; deuterium; b) methyl; c) allyl; d) —CH₂OH; e) aryl; substituted aryl; f) heteroaryl; substituted heteroaryl; and g) —C₁-C₆ alkyl, —C₂-C₆ alkenyl, or —C₂-C₆ alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N, optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; R₂ is selected from the group consisting of: a) hydrogen; b) hydroxy; and c) activated hydroxy; when R₁ is H, R₂ is selected from the group consisting of: a) hydrogen; b) hydroxy; c) activated hydroxy; d) N₃; e) NH₂; f) CN; g) protected hydroxy; h) protected amino; i) -A-R₃, where A is O, O(CO)O, S, S(O), SO₂, NH, NCH₃, NH(CO), NH(CO)O, NH(CO)NH or NHSO₂; and R₃ is independently selected from the group consisting of: (i) hydrogen; (ii) aryl; substituted aryl; heteroaryl; substituted heteroaryl; and (iii) —C₁-C₆ alkyl, —C₂-C₆ alkenyl, or —C₂-C₆ alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N, optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;  provided that when A=S(O) or SO₂, R₃ cannot be hydrogen; and (j)

 wherein E is absent, O, S, S(O), S(O)₂, NR₃, N(CO)R₃, NSO₂R₃, or CHR₃; n=1, 2, or 3; and m=2 or 3, where R₃ is as previously defined; alternatively, R₁ and R₂ taken together with the carbon atom to which they are attached is: a) C═O; b) C(OR₄)(OR₅), where R₄ and R₅ are selected from the group consisting of C₁-C₁₂ alkyl, aryl or substituted aryl; or taken together are —(CH₂)_(m)—, and where m is 2 or 3; c) C(SR₄)(SR₅), where R₄ and R₅ are as previously defined above; d) C═CHR₃, where R₃ is as previously defined; e) C═CNH(amino protecting group); or f) C═N-Z-R₃, where Z is absent, O, NH, NH(CO), NH(CO)NH or NHSO₂; and R₃ is as previously defined; X and Y are: a) when one of X and Y is a hydrogen, the other is selected from: (i) hydrogen; (ii) hydroxy; (iii) activated hydroxy; (iv) N₃; (v) NH₂; (vi) CN; (vii) protected hydroxy; (viii) protected amino; (ix) -A-R₃, where A is O, O(CO)O, S, S(O), SO₂, NH, NCH₃, NH(CO), NH(CO)O, NH(CO)NH or NHSO₂, where R₃ is as previously defined; and (x)

 wherein E is absent, O, S, S(O), S(O)₂, NR₃, N(CO)R₃, NSO₂R₃, or CHR₃; n=1, 2, or 3; and m=2 or 3, where R₃ is as previously defined; b) X, Y taken together with the carbon atom to which they are attached is: (i) C═O; (ii) C═N—OR₆, wherein R₆ is selected from the group consisting of:
 1. hydrogen;
 2. —CH₂O(CH₂)₂OCH₃;
 3. —CH₂O(CH₂O)_(n)CH₃, wherein n is as previously defined;
 4. —C₁-C₁₂ alkyl , containing 0, 1, 2, or 3 heteroatoms, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heteroaryl and substituted heteroaryl;
 5. C₃-C₁₂ cycloalkyl;
 6. C(O)—C₁-C₁₂ alkyl;
 7. C(O)—(C₃-C₁₂ cycloalkyl);
 8. C(O)—R₃, wherein R₃ is as previously defined; and
 9. —Si(R_(a))(R_(b))(R_(c)), wherein R_(a), R_(b) and R_(c) are each independently selected from the group consisting of C₁-C₁₂ alkyl, aryl and substituted aryl; or (iii) C═N—O—C(R₇)(R₈)—O—R₉, wherein R₇ and R₈ taken together with the carbon atom to which they are attached form a C₃ to C₁₂ cycloalkyl group or each independently is selected from the group consisting of: hydrogen and C₁-C₁₂ alkyl; and R₉ is selected from the group consisting of:
 1. —C₁-C₁₂ alkyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heteroaryl and substituted heteroaryl;
 2. —C₃-C₁₂ cycloalkyl; and
 3. —Si(R_(a))(R_(b))(R_(c)), wherein R_(a), R_(b) and R_(c) are as previously defined; B is NR₃₀R₄₀; wherein R₃₀ and R₄₀ is independently selected from the group consisting of hydrogen, acyl, a substituted or unsubstituted, saturated or unsaturated aliphatic group, a substituted or unsubstituted, saturated or unsaturated alicyclic group, a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, saturated or unsaturated heterocyclic group; or can be taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted heterocyclic or heteroaromatic ring; V is selected from the group consisting of hydrogen, azido, cyano, nitro, aldehyde, carboxylic acid, amide, a substituted or unsubstituted, saturated or unsaturated aliphatic group; Q is selected from the group consisting of: (a) hydrogen; (b) protected hydroxy; and (c) OR₂₁, where R₂₁ is selected from the group consisting of: (i) hydrogen; (ii) aryl; substituted aryl; heteroaryl; substituted heteroaryl; (iii) —C₁-C₆ alkyl, —C₂-C₆ alkenyl, or —C₂-C₆ alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N, optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; and (iv) —C₃-C₁₂ cycloalkyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N, optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; L is selected from the group consisting of: (a) —CH₂CH₃; (b) —CH(OH)CH₃; and (c) —C₁-C₆ alkyl, —C₂-C₆ alkenyl, or —C₂-C₆ alkynyl optionally substituted with one or more substituents selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl; Rx is hydrogen, hydroxy protecting group or hydroxy prodrug group.
 2. A compound according to claim 1 represented by formula (II):

where R₁, R₂ and R_(x) are as previously defined in claim
 1. 3. A compound according to claim 1 represented by formula (III):

where R₁, R₂ and R_(x) are as previously defined in claim
 1. 4. A compound according to claim 1 represented by formula (IV):

where R₁, R₂ and R_(x) are as previously defined in claim
 1. 5. A compound according to claim 1 represented by formula (V):

where R₁, R₂ and R_(x) are as previously defined in claim
 1. 6. A compound according to claim 1 represented by formula (VI):

where R₁, R₂ and R_(x) are as previously defined in claim
 1. 7. A compound of claim 2, wherein R₁ and R₂ taken together with the carbon atom to which they are attached are C═CH₂, and Rx=Ac.
 8. A compound of claim 4, wherein R₁ and R₂ taken together with the carbon atom to which they are attached are C═CH₂, and Rx=Ac.
 9. A compound of claim 2, wherein R₁ and R₂ taken together with the carbon atom to which they are attached are C═CH₂, and Rx=H.
 10. A compound of claim 4, wherein R₁ and R₂ taken together with the carbon atom to which they are attached are C═CH₂, and Rx=H.
 11. A compound of claim 3, wherein R₁ and R₂ taken together with the carbon atom to which they are attached are C═CH₂, and Rx=H.
 12. A compound of claim 3, wherein R₁ and R₂ taken together with the carbon atom to which they are attached are C═NO[6′-Amino-[2,2′]bipyridinyl-6-ylmethyl], and Rx=H.
 13. A compound of claim 5, wherein R₁ and R₂ taken together with the carbon atom to which they are attached are C═NO[6′-Amino-[2,2′]bipyridinyl-6-ylmethyl], and Rx=H.
 14. A compound of claim 1 having the Formula A, wherein X and Y are taken together with the carbon to which they are attached (CXY), selected from compounds 8-14 of Table 1: TABLE 1 (A)

Compound CXY Rx (8) C═NOAc Ac (9) C═NOH H (10) C═NH H (11) CH(NH₂) H (12) CH(OH) H (13) C═O H (14) C═O Ac


15. A compound of claim 3, wherein X and Y are taken together with the carbon to which they are attached (CR₁R₂), selected from the compounds 15 to 272 of Table 2: TABLE 2 Compound Cr₁R₂ Rx (15) C═NO[CH₂Ph] Ac (16) C═NO[CH₂Ph] H (17) C═NO[(CH₂)₂Ph] Ac (18) C═NO[(CH₂)₂Ph] H (19) C═NO[(CH₂)₃Ph] Ac (20) C═NO[(CH₂)₃Ph] H (21) C═NO[(CH₂)₄Ph] Ac (22) C═NO[(CH₂)₄Ph] H (23) C═NO[Ph] Ac (24) C═NO[Ph] H (25) C═NO[(CH₂)₅Ph] Ac (26) C═NO[(CH₂)₅Ph] H (27)

Ac (28)

H (29)

Ac (30)

H (31)

Ac (32)

H (33)

Ac (34)

H (35)

Ac (36)

H (37)

Ac (38)

H (39)

Ac (40)

H (41)

H (42)

Ac (43)

H (44)

Ac (45)

H (46)

Ac (47)

H (48)

Ac (49)

H (50)

Ac (51)

H (52)

Ac (53)

H (54)

Ac (55)

H (56)

Ac (57)

H (58)

Ac (59)

H (60)

H (61)

H (62)

Ac (63)

H (64)

Ac (65)

H (66)

Ac (67)

H (68)

Ac (69)

H (70)

Ac (71)

H (72)

Ac (73)

H (74)

Ac (75)

H (76)

Ac (77)

H (78)

Ac (79)

H (80)

Ac (81)

H (82)

Ac (83)

H (84)

Ac (85)

H (86)

Ac (87)

H (88)

Ac (89)

H (90)

Ac (91)

H (92)

Ac (93)

H (94)

Ac (95)

H (96)

Ac (97)

H (98)

Ac (99)

H (100)

Ac (101)

H (102)

Ac (103)

H (104)

Ac (105)

H (106)

Ac (107)

H (108)

Ac (109)

H (110)

Ac (111)

H (112)

Ac (113)

H (114)

Ac (115)

H (116)

Ac (117)

H (118)

Ac (119)

H (120)

Ac (121)

H (122)

Ac (123)

H (124)

Ac (125)

H (126)

Ac (127)

H (128)

Ac (129)

H (130)

Ac (131)

H (132)

Ac (133)

H (134)

Ac (135)

H (136)

Ac (137)

H (138)

Ac (139)

H (140)

Ac (141)

H (142)

Ac (143)

H (144)

Ac (145)

H (146)

Ac (147)

H (148)

Ac (149)

H (150)

Ac (151)

H (152)

Ac (153)

H (154)

Ac (155)

H (156)

Ac (157)

H (158)

H (159)

Ac (160)

H (161)

Ac (162)

H (163)

Ac (164)

H (165)

H (166)

Ac (167)

H (168)

Ac (169)

H (170)

Ac (171)

H (172)

Ac (173)

H (174)

Ac (175)

H (176)

Ac (177)

H (178)

Ac (179)

H (180)

Ac (181)

H (182)

H (183)

Ac (184)

H (185)

Ac (186)

H (187)

Ac (188)

H (189)

Ac (190)

H (191)

Ac (192)

H (193)

Ac (194)

H (195)

Ac (196)

H (197)

Ac (198)

H (199)

H (200)

Ac (201)

H (202)

Ac (203)

H (204)

Ac (205)

H (206)

Ac (207)

H (208)

Ac (209)

H (210)

Ac (211)

H (212)

Ac (213)

H (214)

Ac (215)

H (216)

Ac (217)

H (218)

Ac (219)

H (220)

Ac (221)

H (222)

Ac (223)

H (224)

Ac (225)

H (226)

Ac (227)

H (228)

Ac (229)

H (230)

Ac (231)

H (232)

Ac (233)

H (234)

Ac (235)

H (236)

Ac (237)

H (238)

Ac (239)

H (240)

Ac (241)

H (242)

Ac (243)

H (244)

Ac (245)

H (246)

Ac (247)

H (248)

H (249)

Ac (250)

H (251)

Ac (252)

H (253)

Ac (254)

H (255)

Ac (256)

H (257)

Ac (258)

H (259)

Ac (260)

H (261)

Ac (262)

H (263)

Ac (264)

H (265)

Ac (266)

H (267)

Ac (268)

H (269)

Ac (270)

H (271)

Ac (272)

H


16. A compound of claim 1 having the Formula B, selected from compounds 273-434 of Table 3: TABLE 3 (B)

Compound R₃ (273)

(274)

(275)

(276)

(277)

(278)

(279)

(280)

(281)

(282)

(283)

(284)

(285)

(286)

(287)

(288)

(289)

(290)

(291)

(292)

(293)

(294)

(295)

(296)

(297)

(298)

(299)

(300)

(301)

(302)

(303)

(304)

(305)

(306)

(307)

(308)

(309)

(310)

(311)

(312)

(313)

(314)

(315)

(316)

(317)

(318)

(319)

(320)

(321)

(322)

(323)

(324)

(325)

(326)

(327)

(328)

(329)

(330)

(331)

(332)

(333)

(334)

(335)

(336)

(337)

(338)

(339)

(340)

(341)

(342)

(343)

(344)

(345)

(346)

(347)

(348)

(349)

(350)

(351)

(352)

(353)

(354)

(355)

(356)

(357)

(358)

(359)

(360)

(361)

(362)

(363)

(364)

(365)

(366)

(367)

(368)

(369)

(370)

(371)

(372)

(373)

(374)

(375)

(376)

(377)

(378)

(379)

(380)

(381)

(382)

(383)

(384)

(385)

(386)

(387)

(388)

(389)

(390)

(391)

(392)

(393)

(394)

(395)

(396)

(397)

(398)

(399)

(400)

(401)

(402)

(403)

(404)

(405)

(406)

(407)

(408)

(409)

(410)

(411)

(412)

(413)

(414)

(415)

(416)

(417)

(418)

(419)

(420)

(421)

(422)

(423)

(424)

(425)

(426)

(427)

(428)

(429)

(430)

(431)

(432)

(433)

(434)


17. A method for treating a bacterial infection in a subject in need of such treatment, comprising administering to said subject a therapeutically effective amount of a compound according to claim
 1. 18. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt, ester or prodrug thereof, in combination with a pharmaceutically acceptable carrier.
 19. A method for treating a bacterial infection in a subject, comprising administering to said subject a therapeutically effective amount of a pharmaceutical composition according to claim
 18. 20. A method of treating cystic fibrosis in subject, comprising administering to said subject, a therapeutically effective amount of a pharmaceutical composition of claim
 18. 21. A method of treating inflammation in a subject comprising administering to said subject, therapeutically effective amount of a pharmaceutical composition of claim
 18. 22. A process for preparing a compound of claim 2 comprising the steps of: (a) reacting a compound having a formula:

with

in the presence of a phosphine ligand and Pd(0) catalyst under room temperature to reflux conditions to prepare compounds of the formula:

(b) deprotecting the 2′ and the oxime groups of the compound obtained in step (a), followed by deoximating with an inorganic sulfur oxide salt or an inorganic nitrite salt in the presence of acid to form compound having a formula:

(c) protecting the 2′ hydroxyl and oxidizing the compound obtained in step (b) to form compound having a formula:


23. A process of claim 15 further comprising the step of: (a) reducing the enone double bond of compound of claim 2 with a reducing agent to provide compound having a formula:


24. A process for producing a compound of claim 1 having the formula:

comprising the steps of: (a) oxidative cleavage of the compounds with the following formula:

with an oxidizing reagent to give compounds of the following formula:

(b) reacting the compounds prepared in step (a) with R₃ONH₂, in a presence of a mild acid. 